Ocular tear film peak detection and stabilitzation detection systems and methods for determining tear film layer characteristics

ABSTRACT

Ocular surface interferometry (OSI) devices, systems, and methods are disclosed for peak detection and/or determining stabilization of an ocular tear film. Embodiments disclosed herein also include various image capturing and processing methods and related systems for providing various information about a patient&#39;s ocular tear film (e.g., the lipid and aqueous layers) and a patient&#39;s meibomian glands that can be used to analyze tear film layer thickness(es) (TFLT), and related characteristics as it relates to dry eye.

PRIORITY APPLICATIONS

The present application claims priority to U.S. Provisional PatentApplication Ser. No. 61/904,562 entitled “OCULAR SURFACE INTERFEROMETRY(OSI) SYSTEM AND METHODS FOR IMAGING, PROCESSING, AND/OR DISPLAYING ANOCULAR TEAR FILM AND MEIBOMIAN GLAND FEATURES,” filed on Nov. 15, 2013,which is incorporated herein by reference in its entirety.

The present application is also a continuation-in-part patentapplication of U.S. patent application Ser. No. 14/299,504 entitled“OCULAR SURFACE INTERFEROMETRY (OSI) DEVICES AND SYSTEMS FOR IMAGING,PROCESSING, AND/OR DISPLAYING AN OCULAR TEAR FILM,” filed on Jun. 9,2014, which is incorporated herein by reference in its entirety.

RELATED APPLICATIONS

The present application is related to U.S. patent application Ser. No.11/820,664 entitled “TEAR FILM MEASUREMENT,” filed on Jun. 20, 2007, nowissued as U.S. Pat. No. 7,758,190, which is incorporated herein byreference in its entirety.

The present application is also related to U.S. patent application Ser.No. 11/900,314 entitled “TEAR FILM MEASUREMENT,” filed on Sep. 11, 2007,now issued as U.S. Pat. No. 8,192,026, which is incorporated herein byreference in its entirety.

The present application is also related to U.S. patent application Ser.No. 12/798,325 entitled “OCULAR SURFACE INTERFEROMETRY (OSI) METHODS FORIMAGING, PROCESSING, AND/OR DISPLAYING AN OCULAR TEAR FILM,” filed onApr. 1, 2010, now issued as U.S. Pat. No. 8,545,017, which isincorporated herein by reference in its entirety.

The present application is also related to U.S. patent application Ser.No. 12/798,275 entitled “OCULAR SURFACE INTERFEROMETRY (OSI) DEVICES ANDSYSTEMS FOR IMAGING, PROCESSING, AND/OR DISPLAYING AN OCULAR TEAR FILM,”filed on Apr. 1, 2010, which is incorporated herein by reference in itsentirety.

The present application is also related to U.S. patent application Ser.No. 12/798,326 entitled “OCULAR SURFACE INTERFEROMETRY (OSI) METHODS FORIMAGING AND MEASURING OCULAR TEAR FILM LAYER THICKNESS(ES),” filed onApr. 1, 2010, now issued as U.S. Pat. No. 8,092,023, which isincorporated herein by reference in its entirety.

The present application is also related to U.S. patent application Ser.No. 12/798,324 entitled “OCULAR SURFACE INTERFEROMETRY (OSI) DEVICES ANDSYSTEMS FOR IMAGING AND MEASURING OCULAR TEAR FILM LAYER THICKNESS(ES),”filed on Apr. 1, 2010, now issued as U.S. Pat. No. 8,215,774, which isincorporated herein by reference in its entirety.

The present application is also related to U.S. Provisional PatentApplication Ser. No. 61/819,143 entitled “COMBINATION TEAR FILMINTERFEROMETRY AND MEIBOGRAPHY SYSTEM FOR SIMULTANEOUS DATAACQUISITION,” filed on May 3, 2013, which is incorporated herein byreference in its entirety.

The present application is also related to U.S. Provisional PatentApplication Ser. No. 61/819,201 entitled “LID FLIPPINGTRANS-ILLUMINATOR” filed on May 3, 2013, which is incorporated herein byreference in its entirety.

The present application is related to U.S. patent application Ser. No.13/887,429, filed May 6, 2013 and entitled “APPARATUSES AND METHODS FORDETERMINING TEAR FILM BREAK-UP TIME AND/OR FOR DETECTING LID MARGINCONTACT AND BLINK RATES, PARTICULARLY FOR DIAGNOSING, MEASURING, AND/ORANALYZING DRY EYE CONDITIONS AND SYMPTOMS,” which claims priority toU.S. Provisional Patent Application No. 61/642,719 entitled “APPARATUSESAND METHODS FOR DETERMINING TEAR FILM BREAK-UP TIME AND/OR FOR DETECTINGLID MARGIN CONTACT AND BLINK RATES, PARTICULARLY FOR DIAGNOSING,MEASURING, AND/OR ANALYZING DRY EYE CONDITIONS AND SYMPTOMS,” filed May4, 2012, both of which are incorporated herein by reference in theirentireties.

The present application is related to U.S. Patent Application Ser. No.61/904,788, filed Nov. 15, 2013 and entitled “APPARATUSES AND METHODSFOR DETECTING LID MARGIN CONTACT AND BLINK RATES, PARTICULARLY FORDIAGNOSING, MEASURING AND/OR ANALYZING DRY EYE CONDITIONS AND SYMPTOMS,”which is incorporated herein by reference in its entirety.

The present application is being filed with color versions (3 sets) ofthe drawings discussed and referenced in this disclosure. Color drawingsmore fully disclose the subject matter disclosed herein.

FIELD OF THE DISCLOSURE

The technology of the disclosure relates to imaging an ocular tear film.The technology of the disclosure also relates to measuring ocular tearfilm layer thickness(es), including lipid layer thickness (LLT) and/oraqueous layer thickness (ALT). Imaging the ocular tear film andmeasuring TFLT may be used to diagnose “dry eye,” which may be due toany number of deficiencies, including lipid deficiency and aqueousdeficiency.

BACKGROUND

In the human eye, the precorneal tear film covering ocular surfaces iscomposed of three primary layers: the mucin layer, the aqueous layer,and the lipid layer. Each layer plays a role in the protection andlubrication of the eye and thus affects dryness of the eye or lackthereof. Dryness of the eye is a recognized ocular disease, which isgenerally referred to as “dry eye,” “dry eye syndrome” (DES), or“keratoconjunctivitis sicca” (KCS). Dry eye can cause symptoms, such asitchiness, burning, and irritation, which can result in discomfort.There is a correlation between the ocular tear film layer thicknessesand dry eye disease. The various different medical conditions and damageto the eye as well as the relationship of the aqueous and lipid layersto those conditions are reviewed in Sury Opthalmol 52:369-374, 2007 andadditionally briefly discussed below.

As illustrated in FIG. 1, the precorneal tear film includes an innermostlayer of the tear film in contact with a cornea 10 of an eye 11 known asthe mucus layer 12. The mucus layer 12 is comprised of many mucins. Themucins serve to retain aqueous in the middle layer of the tear filmknown as the aqueous layer. Thus, the mucus layer 12 is important inthat it assists in the retention of aqueous on the cornea 10 to providea protective layer and lubrication, which prevents dryness of the eye11.

A middle or aqueous layer 14 comprises the bulk of the tear film. Theaqueous layer 14 is formed by secretion of aqueous by lacrimal glands 16and accessory tear glands 17 surrounding the eye 11, as illustrated inFIG. 2A. FIG. 2B illustrates the eye 11 in FIG. 2A during a blink. Theaqueous, secreted by the lacrimal glands 16 and accessory tear glands17, is also commonly referred to as “tears.” One function of the aqueouslayer 14 is to help flush out any dust, debris, or foreign objects thatmay get into the eye 11. Another important function of the aqueous layer14 is to provide a protective layer and lubrication to the eye 11 tokeep it moist and comfortable. Defects that cause a lack of sufficientaqueous in the aqueous layer 14, also known as “aqueous deficiency,” area common cause of dry eye. Contact lens wear can also contribute to dryeye. A contact lens can disrupt the natural tear film and can reducecorneal sensitivity over time, which can cause a reduction in tearproduction.

The outermost layer of the tear film, known as the “lipid layer” 18 andalso illustrated in FIG. 1, also aids to prevent dryness of the eye. Thelipid layer 18 is comprised of many lipids known as “meibum” or “sebum”that is produced by meibomian glands 20 in upper and lower eyelids 22,24, as illustrated in FIG. 3. This outermost lipid layer is very thin,typically less than 250 nanometers (nm) in thickness. The lipid layer 18provides a protective coating over the aqueous layer 14 to limit therate at which the aqueous layer 14 evaporates. Blinking causes the uppereyelid 22 to mall up aqueous and lipids as a tear film, thus forming aprotective coating over the eye 11. A higher rate of evaporation of theaqueous layer 14 can cause dryness of the eye. Thus, if the lipid layer18 is not sufficient to limit the rate of evaporation of the aqueouslayer 14, dryness of the eye may result.

Notwithstanding the foregoing, it has been a long standing and vexingproblem for clinicians and scientists to quantify the lipid and aqueouslayers and any deficiencies of same to diagnose evaporative tear lossand/or tear deficiency dry eye conditions. Further, many promisingtreatments for dry eye have failed to receive approval from the UnitedStates Food and Drug Administration due to the inability to demonstrateclinical effectiveness to the satisfaction of the agency. Manyclinicians diagnose dry eye based on patient symptoms alone.Questionnaires have been used in this regard. Although it seemsreasonable to diagnose dry eye based on symptoms alone, symptoms ofocular discomfort represent only one aspect of “dry eyes,” as defined bythe National Eye Institute workshop on dry eyes. In the absence of ademonstrable diagnosis of tear deficiency or a possibility of excessivetear evaporation and damage to the exposed surface of the eye, onecannot really satisfy the requirements of dry eye diagnosis.

SUMMARY

Embodiments of the detailed description include ocular tear film peakdetection and stabilization detection systems and methods fordetermining tear film layer characteristics. Embodiments disclosedherein also include various image capturing and processing methods andrelated systems for providing various information about a patient'socular tear film and their meibomian glands, (e.g., the lipid andaqueous layers) that can be used to analyze TFLT and relatedcharacteristics as it relates to dry eye. Additional embodimentsdisclosed herein also include various information about analyzing andimaging a patient's meibomian gland and various features or structuresof the meibomian gland including the shape, size, continuity,uniformity, and orifice of the gland. In this regard, in one embodiment,an apparatus for peak detection of a tear film layer thickness(es)(TFLT) is provided. The apparatus comprises a control system. Thecontrol system is configured to receive a plurality of images containingoptical wave interference of specularly reflected light from a region ofinterest of an ocular tear film captured by an imaging device whileilluminated by a multi-wavelength light source. The control system isalso configured to convert at least a portion of each image among theplurality of images representing the optical wave interference of thespecularly reflected light from at least a portion of the region ofinterest of the ocular tear film into at least one color-based value.The control system is also configured to measure the TFLT of the atleast a portion of the region of interest of the ocular tear film ineach image among the plurality of images based on a comparison of the atleast one color-based value to a tear film layer optical waveinterference model. The control system is also configured to determine apeak TFLT from a measured TFLT of the at least a portion of the regionof interest of the ocular tear film among the plurality of images. Thecontrol system is also configured to generate a resulting imagecomprising the peak TFLT for the at least a portion of the region ofinterest of the ocular tear film.

In another embodiment, an apparatus for determining tear film stabilityof an ocular tear film is provided. The apparatus comprises a controlsystem. The control system is configured to receive a plurality ofimages containing optical wave interference of specularly reflectedlight from a region of interest of an ocular tear film captured by animaging device while illuminated by a multi-wavelength light source. Thecontrol system is also configured to convert at least a portion of eachimage among the plurality of images representing the optical waveinterference of the specularly reflected light from at least a portionof the region of interest of the ocular tear film into at least onecolor-based value. The control system is also configured to measure atear film layer thickness(es) (TFLT) of the at least a portion of theregion of interest of the ocular tear film in each image among theplurality of images based on a comparison of the at least onecolor-based value to a tear film layer optical wave interference model.The control system is also configured to determine a stabilization timeof the ocular tear film based on the change in the TFLT in the at leasta portion of the region of interest of the ocular tear film in theplurality of images.

In this regard, in embodiments disclosed herein the OSI devices,systems, and methods can be used to measure the thickness of the lipidlayer component (LLT) and/or the aqueous layer component (ALT) of theocular tear film. “TFLT” as used herein includes LLT, ALT, or both LLTand ALT. “Measuring TFLT” as used herein includes measuring LLT, ALT, orboth LLT and ALT. Imaging the ocular tear film and measuring TFLT can beused in the diagnosis of a patient's tear film, including but notlimited to lipid layer and aqueous layer deficiencies. In thedescriptions provided herein, embodiments disclosed may includemeasuring or analyzing the rate or velocity of movement of the TFLT, thepeak velocity of the TFLT, or the three-dimensional (3D) shape of theTFLT. Again, “TFLT” as used herein includes LLT, ALT, or both LLT andALT. In the descriptions provided herein, measuring TFLT can be used toevaluate or analyze the blinking and partial blinking characteristics ofa patient. “Measuring TFLT” as used herein includes measuring LLT, ALT,or both LLT and ALT. These characteristics may be the cause orcontributing factor to a patient experiencing dry eye syndrome (DES).

Other embodiments disclosed herein can include a light source that iscontrolled to direct light in the visible region to an ocular tear film.The light source may be a Lambertian emitter that provides a uniform orsubstantially uniform intensity in all directions of emission. The lightsource is arranged such that light rays emitted from the light sourceare specularly reflected from the tear film and undergo constructive anddestructive optical wave interference interactions (also referred to as“interference interactions”) in the ocular tear film. An imaging devicehaving a detection spectrum that includes the spectrum of the lightsource is focused on an area(s) of interest on the lipid layer of thetear film. The imaging device captures the interference interactions(i.e., modulation) of specularly reflected light rays from theilluminated tear film coming together by the focusing action of theimaging device in a first image. The imaging device then captures theoptical wave interference signals (also referred to as “interferencesignals”) representing the interference interactions of specularlyreflected light from the tear film. The imaging device produces anoutput signal(s) representative of the interference signal in a firstimage. The first image may contain an interference signal for a givenimaged pixel or pixels of the lipid layer by the imaging device.

The first image can be displayed to a technician or other user. Thefirst image can also be processed and analyzed to measure a TFLT in thearea or region of interest of the ocular tear film. In one embodiment,the first image also contains a background signal(s) that does notrepresent specularly reflected light from the tear film which issuperimposed on the interference signal(s). The first image is processedto subtract or substantially subtract out the background signal(s)superimposed upon the interference signal to reduce error before beinganalyzed to measure TFLT. This is referred to as “backgroundsubtraction” in the present disclosure. The separate backgroundsignal(s) includes returned captured light that is not specularlyreflected from the tear film and thus does not contain optical waveinterference information (also referred to as “interferenceinformation”). For example, the background signal(s) may include stray,ambient light entering into the imaging device, scattered light from thepatient's face and eye structures outside and within the tear film as aresult of ambient light and diffuse illumination by the light source,and eye structure beneath the tear film, and particularly contributionfrom the extended area of the source itself. The background signal(s)adds a bias (i.e., offset) error to the interference signal(s) therebyreducing interference signal strength and contrast. This error canadversely influence measurement of TFLT. Further, if the backgroundsignal(s) has a color hue different from the light of the light source,a color shift can also occur to the captured optical wave interference(also referred to as “interference”) of specularly reflected light thusintroducing further error.

Those skilled in the art will appreciate the scope of the presentdisclosure and realize additional aspects thereof after reading thefollowing detailed description of the preferred embodiments inassociation with the accompanying drawing figures.

BRIEF DESCRIPTION OF THE DRAWINGS

The patent or application file contains at least one drawing executed incolor. Copies of this patent or patent application publication withcolor drawing(s) will be provided by the Office upon request and paymentof the necessary fee.

The accompanying drawing figures incorporated in and forming a part ofthis specification illustrate several aspects of the disclosure, andtogether with the description serve to explain the principles of thedisclosure.

FIG. 1 is a side view of an exemplary eye showing the three layers ofthe tear film in exaggerated form;

FIG. 2A is a front view of an exemplary eye showing the lacrimal andaccessory tear glands that produce aqueous in the eye;

FIG. 2B is a front view of an exemplary eye in FIG. 2A during a blink;

FIG. 3 illustrates exemplary upper and lower eyelids showing themeibomian glands contained therein;

FIGS. 4A and 4B are illustrations of an exemplary light source andimaging device to facilitate discussion of illumination of the tear filmand capture of interference interactions of specularly reflected lightfrom the tear film;

FIG. 5 illustrates (in a microscopic section view) exemplary tear filmlayers to illustrate how light rays can specularly reflect from varioustear film layer transitions;

FIG. 6 is a flowchart of an exemplary process for obtaining one or moreinterference signals from images of a tear film representing specularlyreflected light from the tear film with background signal subtracted orsubstantially subtracted;

FIG. 7 illustrates a first image focused on a lipid layer of a tear filmand capturing interference interactions of specularly reflected lightfrom an area or region of interest of the tear film;

FIG. 8 illustrates a second image focused on the lipid layer of the tearfilm in FIG. 7 and capturing background signal when not illuminated bythe light source;

FIG. 9 illustrates an image of the tear film when background signalcaptured in the second image of FIG. 8 is subtracted from the firstimage of FIG. 7;

FIG. 10 is a flowchart of another exemplary optical tiling process forobtaining one or more interference signals from tiled portions in anarea or region of interest of a tear film representing specularlyreflected light from the tear film with background signal subtracted orsubstantially subtracted;

FIG. 11A illustrates a first image focused on the lipid layer of thetear film capturing interference interactions of specularly reflectedlight and background signal from tiled portions in an area or region ofinterest of the tear film;

FIG. 11B illustrates a second image focused on the lipid layer of thetear film in FIG. 11A capturing background signal and interferenceinteractions of specularly reflected light from the tiled portions inthe area or region of interest in FIG. 11A, respectively;

FIG. 12 illustrates an image when the background signal captured indiffusely illuminated tiled portions in the first and second images ofFIGS. 11A and 11B are subtracted or substantially subtracted from thespecularly reflected light in corresponding tiled portions in the firstand second images of FIGS. 11A and 11B;

FIG. 13A illustrates a first image focused on a lipid layer of a tearfilm capturing interference interactions of specularly reflected lightand background signal from concentric tiled portions in an area orregion of interest of the tear film;

FIG. 13B illustrates a second image focused on a lipid layer of the tearfilm in FIG. 13A capturing interference interactions of backgroundsignal and specularly reflected light, respectively, from the concentrictiled portions in the area or region of interest of the tear film inFIG. 13A;

FIG. 14 is a perspective view of an exemplary ocular surfaceinterferometry (OSI) device for illuminating and imaging a patient'stear film, displaying images, analyzing the patient's tear film, andgenerating results from the analysis of the patient's tear film;

FIG. 15 is a side view of the OSI device of FIG. 14 illuminating andimaging a patient's eye and tear film;

FIG. 16 is a side view of a video camera and illuminator within the OSIdevice of FIG. 14 imaging a patient's eye and tear film;

FIG. 17 is a top view of an illumination device provided in the OSIdevice of FIG. 14 illuminating a patient's tear film with the videocamera capturing images of the patient's tear film;

FIG. 18 is a perspective view of an exemplary printed circuit board(PCB) with a plurality of light emitting diodes (LED) provided in theillumination device of the OSI device in FIG. 14 to illuminate thepatient's tear film;

FIG. 19 is a perspective view of the illumination device and housing inthe OSI device of FIG. 14;

FIGS. 20-24 illustrate exemplary light grouping patterns for theillumination device of FIG. 17 that may be used to image tiled patternsof specularly reflected light from a tear film;

FIG. 25A illustrates an exemplary system diagram of a control system andsupporting components in the OSI device of FIG. 14;

FIG. 25B is a flowchart illustrating an exemplary overall processingflow of the OSI device of FIG. 14 having systems components according tothe exemplary system diagram of the OSI device in FIG. 25A;

FIG. 26 is a flowchart illustrating an exemplary process forautopositioning the video camera of the OSI device in FIG. 16 to apatient's eye before capturing images of the ocular tear film to beprocessed and analyzed;

FIG. 27 is a flowchart illustrating an exemplary process forautofocusing the video camera of the OSI device in FIG. 16 to apatient's eye before capturing images of the ocular tear film to beprocessed and analyzed;

FIG. 28 is a flowchart illustrating exemplary pre-processing stepsperformed on the combined first and second images of a patient's tearfilm before measuring tear film layer thickness (TFLT);

FIG. 29 is an exemplary graphical user interface (GUI) for controllingimaging, pre-processing, and post-processing settings of the OSI deviceof FIG. 14;

FIG. 30 illustrates an example of a subtracted image in an area orregion of interest of a tear film containing specularly reflected lightfrom the tear film overlaid on top of a background image of the tearfilm;

FIGS. 31A and 31B illustrate exemplary threshold masks that may be usedto provide a threshold function during pre-processing of a resultingimage containing specularly reflected light from a patient's tear film;

FIG. 32 illustrates an exemplary image of FIG. 30 after a thresholdpre-processing function has been performed leaving interference of thespecularly reflected light from the patient's tear film;

FIG. 33 illustrates an exemplary image of the image of FIG. 32 aftererode and dilate pre-processing functions have been performed on theimage;

FIG. 34 illustrates an exemplary histogram used to detect eye blinksand/or eye movements in captured images or frames of a tear film;

FIG. 35 illustrates an exemplary process for loading an InternationalColour Consortium (ICC) profile and tear film interference model intothe OSI device of FIG. 14;

FIG. 36 illustrates a flowchart providing an exemplary visualizationsystem process for displaying images of a patient's tear film on adisplay in the OSI device of FIG. 14;

FIGS. 37A-37C illustrate exemplary images of a patient's tear film witha tiled pattern of interference interactions from specularly reflectedlight from the tear film displayed on a display;

FIG. 38 illustrates an exemplary post-processing system that may beprovided in the OSI device of FIG. 14;

FIG. 39A illustrates an exemplary 3-wave tear film interference modelbased on a 3-wave theoretical tear film model to correlate differentobserved interference color with different lipid layer thicknesses(LLTs) and aqueous layer thicknesses (ALTs);

FIG. 39B illustrates another exemplary 3-wave tear film interferencemodel based on a 3-wave theoretical tear film model to correlatedifferent observed interference color with different lipid layerthicknesses (LLTs) and aqueous layer thicknesses (ALTs);

FIG. 40 is another representation of the 3-wave tear film interferencemodel of FIGS. 37A and/or FIG. 37B with normalization applied to eachred-green-blue (RGB) color-based value individually;

FIG. 41 is an exemplary histogram illustrating results of a comparisonof interference interactions from the interference signal of specularlyreflected light from a patient's tear film to the 3-wave tear filminterference model of FIGS. 39 and 40 for measuring TFLT of a patient'stear film;

FIG. 42 is an exemplary histogram plot of distances in pixels betweenRGB color-based value representation of interference interactions fromthe interference signal of specularly reflected light from a patient'stear film and the nearest distance RGB color-based value in the 3-wavetear film interference model of FIGS. 39 and 40;

FIG. 43 is an exemplary threshold mask used during pre-processing of thetear film images;

FIG. 44 is an exemplary three-dimensional (3D) surface plot of themeasured LLT and ALT thicknesses of a patient's tear film;

FIG. 45 is an exemplary image representing interference interactions ofspecularly reflected light from a patient's tear film results windowbased on replacing a pixel in the tear film image with the closestmatching RGB color-based value in the normalized 3-wave tear filminterference model of FIG. 40;

FIG. 46 is an exemplary TFLT palette curve for a TFLT palette of LLTsplotted in RGB space for a given ALT in three-dimensional (3D) space;

FIG. 47 is an exemplary TFLT palette curve for the TFLT palette of FIG.46 with LLTs limited to a maximum LLT of 240 nm plotted in RGB space fora given ALT in three-dimensional (3D) space;

FIG. 48 illustrates the TFLT palette curve of FIG. 47 with an acceptabledistance to palette (ADP) filter shown to determine tear film pixelvalues having RGB values that correspond to ambiguous LLTs;

FIG. 49A is a flowchart illustrating an exemplary process for imaging anocular tear film and performing the pre-processing and post-processingprocesses of FIGS. 28 and 38, respectively, and performing additionalfiltering to prepare an image of the ocular tear film for additionalprocessing;

FIG. 49B is a flowchart illustrating exemplary processes for spatiallyand temporally filtering of the pre-processed ocular tear film image;

FIG. 49C is an exemplary weighting map that can be applied to thecolor-based value of neighboring pixels of a pixel of interest for aspatial filtering process;

FIG. 50A is another exemplary image representing interferenceinteractions of specularly reflected light from a patient's tear filmresults after being processed with pre-processing functions;

FIG. 50B is an exemplary psuedocolor representation of the imagerepresenting interference interactions of specularly reflected lightfrom a patient's tear film results in FIG. 50A;

FIG. 51 is a flowchart illustrating an exemplary process of convertingan image representing interference interactions of specularly reflectedlight from a patient's tear film results, such as the image in FIG. 50A,to a psuedocolor representation of the image, such as the image in FIG.50B;

FIG. 52 is an exemplary psuedocolor map illustrating exemplaryconversions of RGB values representing colors of interferenceinteractions of specularly reflected light from a patient's tear filmresults, to psuedocolor RGB values representing psuedocolors for theinterference interactions of specularly reflected light from a patient'stear film results;

FIG. 53 is an exemplary three-dimensional (3D) visualization image of atwo-dimensional (2D) image representing interference interactions ofspecularly reflected light from a patient's tear film results afterbeing processed with pre-processing functions;

FIG. 54 is a flowchart illustrating an exemplary process for convertinga 2D image representing interference interactions of specularlyreflected light from a patient's tear film results into a 3Dvisualization image;

FIG. 55 is a table illustrating an exemplary conversion of LLT to heightvalues used to convert 2D pixels in a 2D image representing interferenceinteractions of specularly reflected light from a patient's tear filmresults into corresponding height values to represent the 2D image intoa 3D visualization image;

FIGS. 56A-56D illustrate exemplary 3D visualization images of a seriesof corresponding 2D images captured over a time period representinginterference interactions of specularly reflected light from a patient'stear film results after being processed with pre-processing functionsover time, to show a 3D visualization of the LLT of the patient's tearfilm over the time period;

FIG. 57A illustrates a series of images illustrating a hypothetical waveof lipids moving across the eye at a given point in space;

FIG. 57B is an image representing exemplary peak values detected over aseries of images of interference interactions of specularly reflectedlight from a patient's tear film results after being processed withpre-processing functions;

FIG. 58 is a flowchart illustrating an exemplary process for convertinga series of images of interference interactions of specularly reflectedlight from a patient's tear film results after being processed withpre-processing functions into an image representing peak values detectedover a series of images of interference interactions of specularlyreflected light from a patient's tear film results after being processedwith pre-processing functions;

FIG. 59 is a table illustrating an exemplary conversion of RGB values ofspecularly reflected light from a patient's tear film results into acorresponding LLT that may be used to determine peak values withinimages of a patient's tear film;

FIGS. 60A-60I are a series of exemplary images representing peak valuesdetected over a series of images of interference interactions ofspecularly reflected light from a patient's tear film results afterbeing processed with pre-processing functions, as peak values changeover time;

FIG. 61 is an exemplary graph that can be displayed on the display ofthe OSI device in FIG. 14 representing a patient's tear film thicknessstabilization following eye blinks;

FIG. 62A is a flowchart illustrating an exemplary process fordetermining a change in a patient's tear film thickness following eyeblinks indicative of a patient's tear film thickness stabilizationfollowing eye blink;

FIG. 62B is a flowchart illustrating another exemplary process fordetermining a change in a patient's tear film thickness following eyeblinks indicative of a patient's tear film thickness stabilizationfollowing eye blink;

FIG. 62C is a flowchart illustrating another exemplary process fordetermining a change in a patient's tear film thickness following eyeblinks indicative of a patient's tear film thickness stabilizationfollowing eye blink;

FIG. 63 is an exemplary image of a patient's eye showing the height ofthe meniscus that can be measured to determine the approximate ALT ofthe patient's tear film;

FIG. 64A-64D are examples of how a surface of an eye can be segmentedfor imaging and analysis purposes according to one or more of thetechniques described in the present disclosure;

FIG. 65A illustrates the eye during a blink;

FIG. 65B illustrates the eye with an increased aperture due to an uppergaze by a patent;

FIG. 65C illustrates an exemplary technique of how to measure anamplitude of a blink of an eye based on the distance an upper eyelid ofthe eye travels during a blink with respect to a pupil of the eye;

FIG. 66 is an exemplary login screen to a user interface system forcontrolling and accessing the OSI device of FIG. 14;

FIG. 67 illustrates an exemplary interface screen for accessing apatient database interface in the OSI device of FIG. 14;

FIG. 68 illustrates a patient action control box for selecting to eithercapture new tear film images of a patient in the patient database orview past captured images of the patient from the OSI device of FIG. 14;

FIG. 69 illustrates a viewing interface for viewing a patient's tearfilm either captured in real-time or previously captured by the OSIdevice of FIG. 14;

FIG. 70 illustrates a tear film image database for a patient;

FIG. 71 illustrates a view images GUI screen showing an overlaid imageof interference interactions of the interference signals from specularlyreflected light from a patient's tear film overtop an image of thepatient's eye for both the patient's left and right eyes side by side;

FIG. 72 illustrates the GUI screen of FIG. 71 with the images of thepatient's eye toggled to show only the interference interactions of theinterference signals from specularly reflected light from a patient'stear film;

DETAILED DESCRIPTION

The embodiments set forth below represent the necessary information toenable those skilled in the art to practice the disclosure andillustrate the best mode of practicing the disclosure. Upon reading thefollowing description in light of the accompanying drawing figures,those skilled in the art will understand the concepts of the disclosureand will recognize applications of these concepts not particularlyaddressed herein. It should be understood that these concepts andapplications fall within the scope of the disclosure and theaccompanying claims.

Embodiments of the detailed description include ocular tear film peakdetection and stabilization detection systems and methods fordetermining tear film layer characteristics. Embodiments disclosedherein also include various image capturing and processing methods andrelated systems for providing various information about a patient'socular tear film and their meibomian glands, (e.g., the lipid andaqueous layers) that can be used to analyze TFLT and relatedcharacteristics as it relates to dry eye. Additional embodimentsdisclosed herein also include various information about analyzing andimaging a patient's meibomian gland and various features or structuresof the meibomian gland including the shape, size, continuity,uniformity, and orifice of the gland.

The OSI devices, systems, and methods can be used to measure thethickness of the lipid layer component (LLT) and/or the aqueous layercomponent (ALT) of the ocular tear film. “TFLT” as used herein includesLLT, ALT, or both LLT and ALT. “Measuring TFLT” as used herein includesmeasuring LLT, ALT, or both LLT and ALT. Measuring TFLT can be used inthe diagnosis of a patient's tear film, including but not limited tolipid layer and aqueous layer deficiencies. These characteristics may bethe cause or contributing factor to a patient experiencing dry eyesyndrome (DES).

In this regard, embodiments disclosed herein can include a light sourcethat is controlled to direct light in the visible region to an oculartear film. For example, the light source may be a Lambertian emitterthat provides a uniform or substantially uniform intensity in alldirections of emission. The light source is arranged such that lightrays emitted from the light source are specularly reflected toward animaging device from the tear film and undergo constructive anddestructive interference interactions in the ocular tear film. Animaging device having a detection spectrum that includes the spectrum ofthe light source is focused on an area(s) of interest on the lipid layerof the tear film. The imaging device captures a first image of theinterference interactions (i.e., modulation) of specularly reflectedlight rays from the illuminated tear film coming together by thefocusing action of the imaging device. The imaging device then capturesthe interference signals representing the interference interactions ofspecularly reflected light from the tear film. The imaging deviceproduces an output signal(s) representative of the interference signalin a first image. The first image may contain an interference signal fora given imaged pixel or pixels of the lipid layer by the imaging device.The output signal(s) can be processed and analyzed to measure a TFLT inthe area or region of interest of the ocular tear film.

In this regard, FIGS. 4A-9 illustrate a general embodiment of an ocularsurface interferometry (OSI) device 30. Other embodiments will bedescribed later in this application. In general, the OSI device 30 isconfigured to illuminate a patient's ocular tear film, capture images ofinterference interactions of specularly reflected light from the oculartear film, and process and analyze the interference interactions tomeasure TFLT. As shown in FIG. 4A, the exemplary OSI device 30positioned in front of one of the patient's eye 32 is shown from a sideview. A top view of the patient 34 in front of the OSI device 30 isillustrated in FIG. 4B. The ocular tear film of a patient's eyes 32 isilluminated with a light source 36 (also referred to herein as“illuminator 36”) and comprises a large area light source having aspectrum in the visible region adequate for TLFT measurement andcorrelation to dry eye. The illuminator 36 can be a white ormulti-wavelength light source.

In this embodiment, the illuminator 36 is a Lambertian emitter and isadapted to be positioned in front of the eye 32 on a stand 38. Asemployed herein, the terms “Lambertian surface” and “Lambertian emitter”are defined to be a light emitter having equal or substantially equal(also referred to as “uniform” or substantially uniform) intensity inall directions. This allows the imaging of a uniformly or substantiallyuniformly bright tear film region for TFLT, as discussed in more detailin this disclosure. The illuminator 36 comprises a large surface areaemitter, arranged such that rays emitted from the emitter are specularlyreflected from the ocular tear film and undergo constructive anddestructive interference in tear film layers therein. An image of thepatient's 34 lipid layer is the backdrop over which the interferenceimage is seen and it should be as spatially uniform as possible.

An imaging device 40 is included in the OSI device 30 and is employed tocapture interference interactions of specularly reflected light from thepatient's 34 ocular tear film when illuminated by the illuminator 36.The imaging device 40 may be a still or video camera, or other devicethat captures images and produces an output signal representinginformation in captured images. The output signal may be a digitalrepresentation of the captured images. The geometry of the illuminator36 can be understood by starting from an imaging lens 42 of the imagingdevice 40 and proceeding forward to the eye 32 and then to theilluminator 36. The fundamental equation for tracing ray lines isSnell's law, which provides:

n1 Sin Θ₁ =n2 Sin Θ₂,

where “n1” and “n2” are the indexes of refraction of two mediumscontaining the ray, and Θ₁ and Θ₂ is the angle of the ray relative tothe normal from the transition surface. As illustrated in FIG. 5, lightrays 44 are directed by the illuminator 36 to an ocular tear film 46. Inthe case of specularly reflected light 48 that does not enter a lipidlayer 50 and instead reflects from an anterior surface 52 of the lipidlayer 50, Snell's law reduces down to Θ₁=Θ₂, since the index ofrefraction does not change (i.e., air in both instances). Under theseconditions, Snell's law reduces to the classical law of reflection suchthat the angle of incidence is equal and opposite to the angle ofreflectance.

Some of the light rays 54 pass through the anterior surface 52 of thelipid layer 50 and enter into the lipid layer 50, as illustrated in FIG.5. As a result, the angle of these light rays 54 (i.e., Θ₃) normal tothe anterior surface 52 of the lipid layer 50 will be different than theangle of the light rays 44 (Θ₁) according to Snell's law. This isbecause the index of refraction of the lipid layer 50 is different thanthe index of refraction of air. Some of the light rays 54 passingthrough the lipid layer 50 will specularly reflect from the lipidlayer-to-aqueous layer transition 56 thereby producing specularlyreflected light rays 58. The specularly reflected light rays 48, 58undergo constructive and destructive interference anterior of the lipidlayer 50. The modulations of the interference of the specularlyreflected light rays 48, 58 superimposed on the anterior surface 52 ofthe lipid layer 50 are collected by the imaging device 40 when focusedon the anterior surface 52 of the lipid layer 50. Focusing the imagingdevice 40 on the anterior surface 52 of the lipid layer 50 allowscapturing of the modulated interference information at the plane of theanterior surface 52. In this manner, the captured interferenceinformation and the resulting calculated TFLT from the interferenceinformation is spatially registered to a particular area of the tearfilm 46 since that the calculated TFLT can be associated with suchparticular area, if desired.

The thickness of the lipid layer 50 (‘d₁’) is a function of theinterference interactions between specularly reflected light rays 48,58. The thickness of the lipid layer 50 (‘d₁’) is on the scale of thetemporal (or longitudinal) coherence of the light source 30. Therefore,thin lipid layer films on the scale of one wavelength of visible lightemitted by the light source 30 offer detectable colors from theinterference of specularly reflected light when viewed by a camera orhuman eye. The colors may be detectable as a result of calculationsperformed on the interference signal and represented as a digital valuesincluding but not limited to a red-green-blue (RGB) value in the RGBcolor space. Quantification of the interference of the specularlyreflected light can be used to measure LLT. The thicknesses of anaqueous layer 60 (‘d₂’) can also be determined using the same principle.Some of the light rays 54 (not shown) passing through the lipid layer 50can also pass through the lipid-to-aqueous layer transition 56 and enterinto the aqueous layer 60 specularly reflecting from theaqueous-to-mucin/cornea layer transition 62. These specular reflectionsalso undergo interference with the specularly reflected light rays 48,58. The magnitude of the reflections from each interface depends on therefractive indices of the materials as well as the angle of incidence,according to Fresnel's equations, and so the depth of the modulation ofthe interference interactions is dependent on these parameters, thus sois the resulting color.

Turning back to FIGS. 4A and 4B, the illuminator 36 in this embodimentis a broad spectrum light source covering the visible region betweenabout 400 nm to about 700 nm. The illuminator 36 contains an arced orcurved housing 64 (see FIG. 4B) into which individual light emitters aremounted, subtending an arc of approximately 130 degrees from the opticalaxis of the eye 32 (see FIG. 4B). A curved surface may present betteruniformity and be more efficient, as the geometry yields a smallerdevice to generating a given intensity of light. The total powerradiated from the illuminator 36 should be kept to a minimum to preventaccelerated tear evaporation. Light entering the pupil can cause reflextearing, squinting, and other visual discomforts, all of which affectTFLT measurement accuracy.

In order to prevent alteration of the proprioceptive senses and reduceheating of the tear film 46, incident power and intensity on the eye 32may be minimized and thus, the step of collecting and focusing thespecularly reflected light may carried out by the imaging device 40. Theimaging device 40 may be a video camera, slit lamp microscope, or otherobservation apparatus mounted on the stand 38, as illustrated in FIGS.4A and 4B. Detailed visualization of the image patterns of the tear film46 involves collecting the specularly reflected light 66 and focusingthe specularly reflected light at the lipid layer 52 such that theinterference interactions of the specularly reflected light from theocular tear film are observable.

Against the backdrop of the OSI device 30 in FIGS. 4A and 4B, FIG. 6illustrates a flowchart discussing how the OSI device 30 can be used toobtain interference interactions of specularly reflected light from thetear film 46, which can be used to measure TFLT. Interferenceinteractions of specularly reflected light from the tear film 46 arefirst obtained and discussed before measurement of TFLT is discussed. Inthis embodiment as illustrated in FIG. 6, the process starts byadjusting the patient 32 with regard to an illuminator 36 and an imagingdevice 40 (block 70). The illuminator 36 is controlled to illuminate thepatient's 34 tear film 46. The imaging device 40 is controlled to befocused on the anterior surface 52 of the lipid layer 50 such that theinterference interactions of specularly reflected light from the tearfilm 46 are collected and are observable. Thereafter, the patient's 34tear film 46 is illuminated by the illuminator 36 (block 72).

The imaging device 40 is then controlled and focused on the lipid layer50 to collect specularly reflected light from an area or region ofinterest on a tear film as a result of illuminating the tear film withthe illuminator 36 in a first image (block 74, FIG. 6). An example ofthe first image by the illuminator 36 is provided in FIG. 7. Asillustrated therein, a first image 79 of a patient's eye 80 is shownthat has been illuminated with the illuminator 36. The illuminator 36and the imaging device 40 may be controlled to illuminate an area orregion of interest 81 on a tear film 82 that does not include a pupil 83of the eye 80 so as to reduce reflex tearing. Reflex tearing willtemporarily lead to thicker aqueous and lipid layers, thus temporarilyaltering the interference signals of specularly reflected light from thetear film 82. As shown in FIG. 7, when the imaging device 40 is focusedon an anterior surface 86 of the lipid layer 88 of the tear film 82,interference interactions 85 of the interference signal of thespecularly reflected light from the tear film 82 as a result ofillumination by the illuminator 36 are captured in the area or region ofinterest 81 in the first image 79. The interference interactions 85appear to a human observer as colored patterns as a result of thewavelengths present in the interference of the specularly reflectedlight from the tear film 82.

However, the background signal is also captured in the first image 79.The background signal is added to the specularly reflected light in thearea or region of interest 81 and included outside the area or region ofinterest 81 as well. Background signal is light that is not specularlyreflected from the tear film 82 and thus contains no interferenceinformation. Background signal can include stray and ambient lightentering into the imaging device 40, scattered light from the patient's34 face, eyelids, and/or eye 80 structures outside and beneath the tearfilm 82 as a result of stray light, ambient light and diffuseillumination by the illuminator 36, and images of structures beneath thetear film 82. For example, the first image 79 includes the iris of theeye 80 beneath the tear film 82. Background signal adds a bias (i.e.,offset) error to the captured interference of specularly reflected lightfrom the tear film 82 thereby reducing its signal strength and contrast.Further, if the background signal has a color hue different from thelight of the light source, a color shift can also occur to theinterference of specularly reflected light from the tear film 82 in thefirst image 79. The imaging device 40 produces a first output signalthat represents the light rays captured in the first image 79. Becausethe first image 79 contains light rays from specularly reflected lightas well as the background signal, the first output signal produced bythe imaging device 40 from the first image 79 will contain aninterference signal representing the captured interference of thespecularly reflected light from the tear film 82 with a bias (i.e.,offset) error caused by the background signal. As a result, the firstoutput signal analyzed to measure TFLT may contain error as a result ofthe background signal bias (i.e., offset) error.

Thus, in this embodiment, the first output signal generated by theimaging device 40 as a result of the first image 79 is processed tosubtract or substantially subtract the background signal from theinterference signal to reduce error before being analyzed to measureTFLT. This is also referred to as “background subtraction.” Backgroundsubtraction is the process of removing unwanted reflections from images.In this regard, the imaging device 40 is controlled to capture a secondimage 90 of the tear film 82 when not illuminated by the illuminator 36,as illustrated by example in FIG. 8. The second image 90 should becaptured using the same imaging device 40 settings and focal point aswhen capturing the first image 79 so that the first image 79 and secondimages 90 forms corresponding image pairs captured within a short timeof each other. The imaging device 40 produces a second output signalcontaining background signal present in the first image 79 (block 76 inFIG. 6). To eliminate or reduce this background signal from the firstoutput signal, the second output signal is subtracted from the firstoutput signal to produce a resulting signal (block 77 in FIG. 6). Theimage representing the resulting signal in this example is illustratedin FIG. 9 as resulting image 92. Thus, in this example, backgroundsubtraction involves two images 79, 90 to provide a frame pair where thetwo images 79, 90 are subtracted from each other, whereby specularreflection from the tear film 82 is retained, and while diffusereflections from the iris and other areas are removed in whole or part.

As illustrated in FIG. 9, the resulting image 92 contains an image ofthe isolated interference 94 of the specularly reflected light from thetear film 82 with the background signal eliminated or reduced (block 78in FIG. 6). In this manner, the resulting signal (representing theresulting image 92 in FIG. 9) includes an interference signal havingsignal improved purity and contrast in the area or region of interest 81on the tear film 82. As will be discussed later in this application, theresulting signal provides for accurate analysis of interferenceinteractions from the interference signal of specular reflections fromthe tear film 82 to in turn accurately measure TFLT. Any method ordevice to obtain the first and second images of the tear film 82 andperform the subtraction of background signal in the second image 90 fromthe first image 79 may be employed. Other specific examples arediscussed throughout the remainder of this application.

An optional registration function may be performed between the firstimage(s) 79 and the second image(s) 90 before subtraction is performedto ensure that an area or point in the second image(s) 90 to besubtracted from the first image(s) 79 is for an equivalent orcorresponding area or point on the first image(s) 79. For example, a setof homologous points may be taken from the first and second images 79,90 to calculate a rigid transformation matrix between the two images.The transformation matrix allows one point on one image (e.g., x1, y1)to be transformed to an equivalent two-dimensional (2D) image on theother image (e.g., x2, y2). For example, the Matlab® function “cp2tform”can be employed in this regard. Once the transformation matrix isdetermined, the transformation matrix can be applied to every point inthe first and second images, and then each re-interpolated at theoriginal points. For example, the Matlab® function “imtransform” can beemployed in this regard. This allows a point from the second image(e.g., x2, y2) to be subtracted from the correct, equivalent point(e.g., x1, y1) on the first image(s) 79, in the event there is anymovement in orientation or the patient's eye between the capture of thefirst and second images 79, 90. The first and second images 79, 90should be captured close in time.

Note that while this example discusses a first image and a second imagecaptured by the imaging device 40 and a resulting first output signaland second output signal, the first image and the second image maycomprise a plurality of images taken in a time-sequenced fashion. If theimaging device 40 is a video camera, the first and second images maycontain a number of sequentially-timed frames governed by the frame rateof the imaging device 40. The imaging device 40 produces a series offirst output signals and second output signals. If more than one imageis captured, the subtraction performed in a first image should ideallybe from a second image taken immediately after the first image so thatthe same or substantially the same lighting conditions exist between theimages so the background signal in the second image is present in thefirst image. The subtraction of the second output signal from the firstoutput signal can be performed in real time. Alternatively, the firstand second output signals can be recorded and processed at a later time.The illuminator 36 may be controlled to oscillate off and on quickly sothat first and second images can be taken and the second output signalsubtraction from the first output signal be performed in less than onesecond. For example, if the illuminator 36 oscillates between on and offat 30 Hz, the imaging device 40 can be synchronized to capture images ofthe tear film 46 at 60 frames per second (fps). In this regard, thirty(30) first images and thirty (30) second images can be obtained in onesecond, with each pair of first and second images taken sequentially.

After the interference of the specularly reflected light is captured anda resulting signal containing the interference signal is produced andprocessed, the interference signal or representations thereof can becompared against a tear film layer interference model to measure TFLT.The interference signal can be processed and converted by the imagingdevice into digital red-green-blue (RGB) component values which can becompared to RGB component values in a tear film interference model tomeasure tear film TFLT. The tear film interference model is based onmodeling the lipid layer of the tear film in various LLTs andrepresenting resulting interference interactions in the interferencesignal of specularly reflected light from the tear film model whenilluminated by the light source. The tear film interference model can bea theoretical tear film interference model where the particular lightsource, the particular imaging device, and the tear film layers aremodeled mathematically, and the resulting interference signals for thevarious LLTs recorded when the modeled light source illuminates themodeled tear film layers recorded using the modeled imaging device. Thesettings for the mathematically modeled light source and imaging deviceshould be replicated in the illuminator 36 and imaging device 40 used inthe OSI device 30. Alternatively, the tear film interference model canbe based on a phantom tear film model, comprised of physical phantomtear film layers wherein the actual light source is used to illuminatethe phantom tear film model and interference interactions in theinterference signal representing interference of specularly reflectedlight are empirically observed and recorded using the actual imagingdevice.

The aqueous layer may be modeled in the tear film interference model tobe of an infinite, minimum, or varying thickness. If the aqueous layeris modeled to be of an infinite thickness, the tear film interferencemodel assumes no specular reflections occur from the aqueous-to-mucinlayer transition 62 (see FIG. 5). If the aqueous layer 62 is modeled tobe of a certain minimum thickness (e.g., >2 μm), the specular reflectionfrom the aqueous-to-mucin layer transition 62 may be considerednegligible on the effect of the convolved RGB signals produced by theinterference signal. In either case, the tear film interference modelwill only assume and include specular reflections from thelipid-to-aqueous layer transition 56. Thus, these tear film interferencemodel embodiments allow measurement of LLT regardless of ALT. Theinterference interactions in the interference signal are compared to theinterference interactions in the tear film interference model to measureLLT.

Alternatively, if the aqueous layer 60 is modeled to be of varyingthicknesses, the tear film interference model additionally includesspecular reflections from the aqueous-to-mucin layer transition 62 inthe interference interactions. As a result, the tear film interferencemodel will include two-dimensions of data comprised of interferenceinteractions corresponding to various LLT and ALT combinations. Theinterference interactions from the interference signal can be comparedto interference interactions in the tear film interference model tomeasure both LLT and ALT. More information regarding specific tear filminterference models will be described later in this application.

In the above described embodiment in FIGS. 6-9, the second image 90 ofthe tear film 82 containing background signal is captured when notilluminated by the illuminator 36. Only ambient light illuminates thetear film 82 and eye 80 structures beneath. Thus, the second image 90and the resulting second output signal produced by the imaging device 40from the second image 90 does not include background signal resultingfrom scattered light from the patient's face and eye structures as aresult of diffuse illumination by the illuminator 36. Only scatteredlight resulting from ambient light is included in the second image 90.However, scattered light resulting from diffuse illumination by theilluminator 36 is included in background signal in the first image 79containing the interference interactions of specularly reflected lightfrom the tear film 82. Further, because the first image 79 is capturedwhen the illuminator 36 is illuminating the tear film, the intensity ofthe eye structures beneath the tear film 82 captured in the first image79, including the iris, are brighter than captured in the second image90. Thus, in other embodiments described herein, the imaging device 40is controlled to capture a second image of the tear film 82 whenobliquely illuminated by the illuminator 36. As a result, the capturedsecond image additionally includes background signal from scatteredlight as a result of diffuse illumination by the illuminator 36 as wellas a higher intensity signal of the eye directly illuminated structuresbeneath the tear film 82. Thus, when the second output signal issubtracted from the first output signal, the higher intensity eyestructure background and the component of background signal representingscattered light as a result of diffuse illumination by the illuminator36, as well as ambient and stray light, are subtracted or substantiallysubtracted from the resulting signal thereby further increasing theinterference signal purity and contrast in the resulting signal. Theresulting signal can then be processed and analyzed to measure TFLT, aswill be described in detail later in this application.

In this regard, FIGS. 10-12 illustrate an embodiment for illuminatingand capturing interference of specularly reflected light from the tearfilm. In this embodiment, the second image is captured when the tearfilm is obliquely illuminated by the illuminator 36 using illuminationthat possesses the same or nearly the same average geometry andilluminance level as used to produce specularly reflected light from atear film. In this manner, the background signal captured in the secondimage contains the equivalent background signal present in the firstimage including scattered light from the tear film and patient's eye asa result of diffuse illumination by the illuminator 36. The second imagealso includes a representative signal of eye structure beneath the tearfilm because of the equivalent lighting when the illuminator 36 isactivated when capturing the second image. In this embodiment, a “tiled”or “tiling” illumination of the tear film is provided. Tiling allows alight source to illuminate a sub-area(s) of interest on the tear film toobtain specularly reflected light while at the same time diffuselyilluminating adjacent sub-area(s) of interest of the tear film to obtainscattered light as a result of diffuse illumination by the illuminator36. In this manner, the subtracted background signal includes scatteredlight as a result of diffuse illumination by the illuminator 36 to allowfurther reduction of offset bias (i.e., offset) error and to therebyincrease interference signal purity and contrast.

In this regard, as illustrated in FIG. 10, the process starts byadjusting the patient 34 with regard to the illuminator 36 and theimaging device 40 (block 100). The illuminator 36 is controlled toilluminate the patient's 34 tear film. The imaging device 40 is locatedappropriately and is controlled to be focused on the lipid layer suchthat the interference interactions of specularly reflected light fromthe tear film are observable when the tear film is illuminated.Thereafter, the lighting pattern of the illuminator 36 is controlled ina first “tiling” mode to produce specularly reflected light from a firstarea(s) of interest of the tear film while diffusely illuminating anadjacent, second area(s) of interest of the tear film (block 102). Aswill be discussed in more detail later in this application, theilluminator 36 may be controlled to turn on only certain lightingcomponents in the illuminator 36 to control the lighting pattern. Aswill be further discussed, the lighting pattern can also be directed tothe meibomian glands directly, the transillumination of the meibomianglands, and the characteristics of the patient's blinking or partialblinking.

An example of a first image 120 captured of a patient's eye 121 and tearfilm 123 by the imaging device 40 when the illuminator 36 produces alight pattern in the first mode is illustrated by example in FIG. 11A.In this example, the illuminator 36 is controlled to provide a firsttiled illumination pattern in an area or region of interest 122 on thetear film 123. While illumination of the tear film 123 in the firstmode, the imaging device 40 captures the first image 120 of thepatient's eye 121 and the tear film 123 (block 104). As illustrated inFIG. 11A, the first image 120 of the patient's eye 121 has beenilluminated so that specularly reflected light is produced in firstportions 126A in the area or region of interest 122 of the tear film123. The interference signal(s) from the first portions 126A includeinterference from specularly reflected light along with additivebackground signal, which includes scattered light signal as a result ofdiffuse illumination from the illuminator 36. Again, the illuminator 36and the imaging device 140 may be controlled to illuminate the tear film123 that does not include the pupil of the eye 121 so as to reducereflex tearing. The illuminator 36 may be flashed in block 102 toproduce specularly reflected light from the first portions 126A, wherebythe imaging device 40 is synchronized with the flashing of theilluminator 36 in block 104 to capture the first image 120 of thepatient's eye 121 and the tear film 123.

Also during the first mode, the illuminator 36 light pattern obliquelyilluminates second, adjacent second portions 128A to the first portions126A in the area or region of interest 122, as shown in the first image120 in FIG. 11A. The second portions 128A include comparable backgroundoffset present in the first portion(s) 126A, which includes scatteredlight signal as a result of diffuse illumination from the illuminator 36since the illuminator 36 is turned on when the first image 120 iscaptured by the imaging device 40. Further, the eye 121 structuresbeneath the tear film 123 are captured in the second portions 128A dueto the diffuse illumination by the illuminator 36. This is opposed tothe second image 90 of FIG. 9, where diffuse illumination by theilluminator 36 is not provided to the tear film when the second image 90is obtained. Thus, in this embodiment, the area or region of interest122 of the tear film 123 is broken into two portions at the same time:first portions 126A producing specularly reflected light combined withbackground signal, and second portions 128A diffusedly illuminated bythe illuminator 36 and containing background signal, which includesscattered light from the illuminator 36. The imaging device 40 producesa first output signal that contains a representation of the firstportions 126A and the second portions 128A.

Next, the illuminator 36 is controlled in a second mode to reverse thelighting pattern from the first mode when illuminating the tear film 123(block 106, FIG. 10). A second image 130 is captured of the tear film121 is captured in the second mode of illumination, as illustrated byexample in FIG. 11B (block 108, FIG. 10). As shown in the second image130 in FIG. 11B, the second portions 128A in the first image 120 of FIG.11A are now second portions 128B in the second image 130 in FIG. 11Bcontaining specularly reflected light from the tear film 123 withadditive background signal. The first portions 126A in the first image120 of FIG. 11A are now first portions 126B in the second image 130 inFIG. 11B containing background signal without specularly reflectedlight. Again, the background signal in the first portions 126B includesscattered light signal as a result of diffuse illumination by theilluminator 36. The imaging device 40 produces a second output signal ofthe second image 130 in FIG. 11B. The illuminator 36 may also be flashedin block 106 to produce specularly reflected light from the secondportions 128B, whereby the imaging device 40 is synchronized with theflashing of the illuminator 36 in block 106 to capture the second image130 of the patient's eye 121 and the tear film 123.

The first and second output signals can then be combined to produce aresulting signal comprised of the interference signal of the specularlyreflected light from the tear film 123 with background signal subtractedor substantially removed from the interference signal (block 110, FIG.10). A resulting image is produced as a result having interferenceinformation from the specularly reflected light from the area or regionof interest 122 of the tear film 123 with background signal eliminatedor reduced, including background signal resulting from scattered lightfrom diffuse illumination by the illuminator 36 (block 112, FIG. 10). Anexample of a resulting image 132 in this regard is illustrated in FIG.12. The resulting image 132 represents the first output signalrepresented by the first image 120 in FIG. 11A combined with the secondoutput signal represented by the second image 130 in FIG. 11B. Asillustrated in FIG. 12, interference signals of specularly reflectedlight from the tear film 123 are provided for both the first and secondportions 126, 128 in the area or region of interest 122. The backgroundsignal has been eliminated or reduced. As can be seen in FIG. 12, thesignal purity and contrast of the interference signal representing thespecularly reflected light from the tear film 123 from first and secondportions 126, 128 appears more vivid and higher in contrast than theinterference interaction 94 in FIG. 9, for example.

In the discussion of the example first and second images 120, 130 inFIGS. 11A and 11B above, each first portion 126 can be thought of as afirst image, and each second portion 128 can be thought of as a secondimage. Thus, when the first and second portions 126A, 128B are combinedwith corresponding first and second portions 126B, 128A, this is akin tosubtracting second portions 126B, 128A from the first portions 12A,128B, respectively.

In the example of FIGS. 10-12, the first image and second images 120,130 contain a plurality of portions or tiles. The number of tilesdepends on the resolution of lighting interactions provided for andselected for the illuminator 36 to produce the first and second modes ofillumination to the tear film 123. The illumination modes can go fromone extreme of one tile to any number of tiles desired. Each tile can bethe size of one pixel in the imaging device 40 or areas covering morethan one pixel depending on the capability of the illuminator 36 and theimaging device 40. The number of tiles can affect accuracy of theinterference signals representing the specularly reflected light fromthe tear film. Providing too few tiles in a tile pattern can limit therepresentative accuracy of the average illumination geometry thatproduces the scattered light signal captured by the imaging device 40 inthe portions 128A and 126B for precise subtraction from portions 128Band 126A respectively.

Note that while this example in FIGS. 10-12 discusses a first image anda second image captured by the imaging device 40 and a resulting firstoutput signal and second output signal, the first image and the secondimage may comprise a plurality of images taken in a time-sequencedfashion. If the imaging device 40 is a video camera, the first andsecond images may contain a number of sequentially-timed frames governedby the frame rate of the imaging device 40. The imaging device 40produces a series of first output signals and second output signals. Ifmore than one image is captured, the subtraction performed in a firstimage should ideally be from a second image taken immediately after thefirst image so that the same or substantially the same lightingconditions exist between the images so the background signal in thesecond image is present in the first image, and more importantly, sothat movement of the eye and especially of the tear-film dynamic isminimal between subtracted frames. The subtraction of the second outputsignal from the first output signal can be performed in real time.Alternatively, the first and second output signals can be recorded andprocessed at a later time.

Other optical tiling patterns are possible other than the “teeth” styletiling pattern illustrated in FIGS. 11A-12. FIGS. 13A and 13B illustratean alternative tiling mode embodiment via illustrations of images of aneye 140 and tear film 142. In this embodiment, a concentric opticaltiling pattern is provided by the illuminator 36 for illuminating thetear film 142. The interference interactions of the specularly reflectedlight from the tear film 142 are captured by the imaging device 40. Asillustrated in FIG. 13A, a first image 144 is taken of an area or regionof interest 146 on the tear film 142 during a first mode of theilluminator 36. The illuminator 36 is controlled to produce a firstlighting pattern in the first mode such that a center portion 148 of thearea or region of interest 146 of the tear film 142 produces specularlyreflected light from the tear film 142. The center portion 148 includesspecularly reflected light from the tear film 142 along with backgroundsignal, including scattered light signal from diffuse illumination ofthe tear film 142 by the illuminator 36. Background signal is producedfrom the edge portions 152 of the area or region of interest 146. Theimaging device 140 produces a first output signal representative of thefirst image 144 in FIG. 13A.

In a second mode of the illuminator 36, as illustrated by therepresentative second image 160 in FIG. 13B, the illuminator 36 iscontrolled to reverse the lighting pattern for illuminating the tearfilm 142 from the first mode. Specularly reflected light is now producedfrom the edge portions 152 in the area or region of interest 146, whichincludes additive background signal. The center portion 148 now producesonly background signal. In this manner, the center portion 148 and theedge portions 152 are concentric portions. The imaging device 40produces a second output signal representative of the second image 160in FIG. 13B.

The first and second output signals can then be combined to produce aresulting signal comprised of the interference signal of the specularlyreflected light from the tear film 142 for the entire area or region ofinterest 146 with background signal subtracted or substantially removedfrom the interference signal. A resulting image (not shown) similar toFIG. 12 can be produced as a result of having interference informationfrom the specularly reflected light from the area or region of interest146 from the tear film 142 with background signal eliminated or reduced,including background signal resulting from scattered light from diffuseillumination by the illuminator 36. The resulting image can then beprocessed and analyzed to measure TFLT. In the example of FIGS. 13A and13B, the illuminator 36 is controlled in the first and second modes suchthat the relationship of the areas between the center portion 148 andthe edge portion 152 is balanced to be approximately 50%/50% so that anequal balance of diffuse illumination from the illuminator 36 isprovided in both modes to portions of the tear film 142 that do notproduce specularly reflected light. However, other balance percentagescan be employed.

Alternatively, a small-scale scanning of the ocular tear film can beemployed to obtain interference of specularly reflected light from thetear film to obtain a high signal strength and contrast of aninterference signal without providing tiled illumination patterns ordiffuse light from the illuminator 36. For example, the area or regionof interest imaged on the ocular tear film could be made very small downto the lowest resolution of the imaging device 40 (e.g., one pixel). Inthis manner, virtually no diffuse illumination is provided from theilluminator 36 to the area or region of interest on the patient's tearfilm when illuminated. Background signal captured in the image of thespecularly reflected light from the tear film would be negligiblecompared to the level of specularly reflected light captured in theimage. Thus, no subtraction of multiple images may need to be performed.The illuminator 36 would be controlled to scan the desired portions ofthe tear film for sequential image capture, with each scan capturing animage of specularly reflected light from a small area or region ofinterest. Each scanned image can then be assembled to produce an overallimage of specularly reflected light from the tear film with negligiblebackground signal and processed and analyzed to measure TFLT.

Exemplary OSI Device

The above discussed illustrations provide examples of illuminating andimaging a patient's TFLT. These principles are described in more detailwith respect to a specific example of an OSI device 170 illustrated inFIGS. 14-50 and described below throughout the remainder of thisapplication. The OSI device 170 can illuminate a patient's tear film,capture interference information from the patient's tear film, andprocess and analyze the interference information to measure TFLT.Further, the OSI device 170 includes a number of optional pre-processingfeatures that may be employed to process the interference signal in theresulting signal to enhance TFLT measurement. The OSI device 170 mayinclude a display and user interface to allow a physician or technicianto control the OSI device 170 to image a patient's eye and tear film andmeasure the patient's TFLT.

Illumination and Imaging

In this regard, FIG. 14 illustrates a perspective view of the OSI device170. The OSI device 170 is designed to facilitate imaging of thepatient's ocular tear film and processing and analyzing the images todetermine characteristics regarding a patient's tear film. The OSIdevice 170 includes an imaging device and light source in this regard,as will be described in more detail below. As illustrated in FIG. 14,the OSI device 170 is comprised generally of a housing 172, a displaymonitor (“display”) 174, and a patient head support 176. The housing 172may be designed for table top placement. The housing 172 rests on a base178 in a fixed relationship. As will be discussed in more detail below,the housing 172 houses an imaging device and other electronics,hardware, and software to allow a clinician to image a patient's oculartear film. A light source 173 (also referred to herein as “illuminator173”) is also provided in the housing 172 and provided behind adiffusing translucent window 175. The translucent window 175 may be aflexible, white, translucent acrylic plastic sheet.

To image a patient's ocular tear film, the patient places his or herhead in the patient head support 176 and rests his or her chin on a chinrest 180. The chin rest 180 can be adjusted to align the patient's eyeand tear film with the imaging device inside the housing 172, as will bediscussed in more detail below. The chin rest 180 may be designed tosupport up to two (2) pounds of weight, but such is not a limitingfactor. A transparent window 177 allows the imaging device inside thehousing 172 to have a clear line of sight to a patient's eye and tearfilm when the patient's head is placed in the patient head support 176.The OSI device 170 is designed to image one eye at a time, but can beconfigured to image both eyes of a patient, if desired.

In general, the display 174 provides input and output from the OSIdevice 170. For example, a user interface can be provided on the display174 for the clinician to operate the OSI device 170 and to interact witha control system provided in the housing 172 that controls the operationof the OSI device 170, including an imaging device, an imaging devicepositioning system, a light source, other supporting hardware andsoftware, and other components. For example, the user interface canallow control of imaging positioning, focus of the imaging device, andother settings of the imaging device for capturing images of a patient'socular tear film. The control system may include a general purposemicroprocessor or computer with memory for storage of data, includingimages of the patient's eye and tear film. The microprocessor should beselected to provide sufficient processing speed to process images of thepatient's tear film and generate output characteristic information aboutthe tear film (e.g., one minute per twenty second image acquisition).The control system may control synchronization of activation of thelight source and the imaging device to capture images of areas ofinterest on the patient's ocular tear film when properly illuminated.Various input and output ports and other devices can be provided,including but not limited to a joystick for control of the imagingdevice, USB ports, wired and wireless communication including Ethernetcommunication, a keyboard, a mouse, speaker(s), etc. A power supply isprovided inside the housing 172 to provide power to the componentstherein requiring power. A cooling system, such as a fan, may also beprovided to cool the OSI device 170 from heat generating componentstherein.

The display 174 is driven by the control system to provide informationregarding a patient's imaged tear film, including TFLT. The display 174also provides a graphical user interface (GUI) to allow a clinician orother user to control the OSI device 170. To allow for human diagnosisof the patient's tear film, images of the patient's ocular tear filmtaken by the imaging device in the housing 172 can also be displayed onthe display 174 for review by a clinician, as will be illustrated anddescribed in more detail below. The images displayed on the display 174may be real-time images being taken by the imaging device, or may bepreviously recorded images stored in memory. To allow for differentorientations of the OSI device 170 to provide a universal configurationfor manufacturing, the display 174 can be rotated about the base 178.The display 174 is attached to a monitor arm 182 that is rotatable aboutthe base 178, as illustrated. The display 174 can be placed opposite ofthe patient head support 176, as illustrated in FIG. 14, if theclinician desires to sit directly across from the patient.Alternatively, display 174 can be rotated either left or right about theX-axis to be placed adjacent to the patient head support 176. Thedisplay 174 may be a touch screen monitor to allow a clinician or otheruser to provide input and control to the control system inside thehousing 172 directly via touch of the display 174 for control of the OSIdevice 170. The display 174 illustrated in FIG. 14 is a fifteen inch(15″) flat panel liquid crystal display (LCD). However, the display 174may be provided of any type or size, including but not limited to acathode ray tube (CRT), plasma, LED, OLED, projection system, etc.

FIG. 15 illustrates a side view of the OSI device 170 of FIG. 14 tofurther illustrate imaging of a patient's eye and ocular tear film. Asillustrated therein, a patient places their head 184 in the patient headsupport 176. More particularly, the patient places their forehead 186against a headrest 188 provided as part of the patient head support 176.The patient places their chin 190 in the chin rest 180. The patient headsupport 176 is designed to facilitate alignment of a patient's eye 192with the OSI device 170, and in particular, an imaging device 194 (andilluminator) shown as being provided inside the housing 172. The chinrest 180 can be adjusted higher or lower to move the patient's eye 192with respect to the OSI device 170.

As shown in FIG. 16, the imaging device 194 is used to image thepatient's ocular tear film to determine characteristics of the patient'stear film. In particular, the imaging device 194 is used to captureinterference interactions of the specularly reflected light from thepatient's tear film when illuminated by a light source 196 (alsoreferred to herein as “illuminator 196”) as well as background signal.As previously discussed, background signal may be captured when theilluminator 196 is illuminating or not illuminating a patient's tearfilm. In the OSI device 170, the imaging device 194 is the “The ImagingSource” model DFK21BU04 charge coupling device (CCD) digital videocamera 198, but many types of metrological grade cameras or imagingdevices can be provided. A CCD camera enjoys characteristics ofefficient light gathering, linear behavior, cooled operation, andimmediate image availability. A linear imaging device is one thatprovides an output signal representing a captured image which isprecisely proportional to the input signal from the captured image.Thus, use of a linear imaging device (e.g., gamma correction set to 1.0,or no gamma correction) provides undistorted interference data which canthen be analyzed using linear analysis models. In this manner, theresulting images of the tear film do not have to be linearized beforeanalysis, thus saving processing time. Gamma correction can then beadded to the captured linear images for human-perceptible display on anon-linear display 174 in the OSI device 170. Alternatively, theopposite scenario could be employed. That is, a non-linear imagingdevice or non-linear setting would be provided to capture tear filmimages, wherein the non-linear data representing the interferenceinteractions of the interference signal can be provided to a non-lineardisplay monitor without manipulation to display the tear film images toa clinician. The non-linear data would be linearized for tear filmprocessing and analysis to estimate tear film layer thickness.

The video camera 198 is capable of producing lossless full motion videoimages of the patient's eye. As illustrated in FIG. 16, the video camera198 has a depth of field defined by the angle between rays 199 and thelens focal length that allows the patient's entire tear film to be infocus simultaneously. The video camera 198 has an external triggersupport so that the video camera 198 can be controlled by a controlsystem to image the patient's eye. The video camera 198 includes a lensthat fits within the housing 172. The video camera 198 in thisembodiment has a resolution of 640×480 pixels and is capable of framerates up to sixty (60) frames per second (fps). The lens system employedin the video camera 198 images a 16×12 mm dimension in a sample planeonto an active area of a CCD detector within the video camera 198. As anexample, the video camera 198 may be the DBK21AU04 Bayer VGA (640×480)video camera using a Pentax VS-LD25 Daitron 25-mm fixed focal lengthlens. Other camera models with alternate pixel size and number,alternate lenses, (etc) may also be employed.

Although a video camera 198 is provided in the OSI device 170, a stillcamera could also be used if the frame rate is sufficiently fast enoughto produce high quality images of the patient's eye. High frame rate inframes per second (fps) facilitate high quality subtraction ofbackground signal from a captured interference signal representingspecularly reflected light from a patient's tear film, and may provideless temporal (i.e., motion) artifacts (e.g., motion blurring) incaptured images, resulting in high quality captured images. This isespecially the case since the patient's eye may move irregularly as wellas blinking, obscuring the tear film from the imaging device duringexamination.

A camera positioning system 200 is also provided in the housing 172 ofthe OSI device 170 to position the video camera 198 for imaging of thepatient's tear film. The camera positioning system 200 is under thecontrol of a control system. In this manner, a clinician can manipulatethe position of the video camera 198 to prepare the OSI device 170 toimage the patient's tear film. The camera positioning system 200 allowsa clinician and/or control system to move the video camera 198 betweendifferent patients' eyes 192, but can also be designed to limit therange of motion within designed tolerances. The camera positioningsystem 200 also allows for fine tuning of the video camera 198 position.The camera positioning system 200 includes a stand 202 attached to abase 204. A linear servo or actuator 206 is provided in the camerapositioning system 200 and connected between the stand 202 and a cameraplatform 207 supporting the video camera 198 to allow the video camera198 to be moved in the vertical (i.e., Y-axis) direction.

In this embodiment of the OSI device 170, the camera positioning system200 may not allow the video camera 198 to be moved in the X-axis or theZ-axis (in and out of FIG. 16), but the disclosure is not so limited.The illuminator 196 is also attached to the camera platform 207 suchthat the illuminator 196 maintains a fixed geometric relationship to thevideo camera 198. Thus, when the video camera 198 is adjusted to thepatient's eye 192, the illuminator 196 is automatically adjusted to thepatient's eye 192 in the same regard as well. This may be important toenforce a desired distance (d) and angle of illumination (Φ) of thepatient's eye 192, as illustrated in FIG. 16, to properly capture theinterference interactions of the specularly reflected light from thepatient's tear film at the proper angle of incidence according toSnell's law, since the OSI device 170 is programmed to assume a certaindistance and certain angles of incidence. In the OSI device 170 in FIG.16, the angle of illumination (Φ) of the patient's eye 192 relative tothe camera 198 axis is approximately 30 degrees at the center of theilluminator 196 and includes a relatively large range of angles fromabout 5 to 60 degrees, but any angle may be provided.

FIGS. 17-20 provide more detail on the illuminator 196. As illustratedin FIG. 17, the exemplary illuminator 196 is provided on an arcedsurface 208 (see also, FIGS. 17-18) of approximately 75 degrees toprovide a large area, broad spectrum light source covering the visibleregions of approximately 400 nanometers (nm) to 700 nm. In thisembodiment, the arced surface 208 has a radius to an imaginary center ofapproximately 190 mm (“r” in FIG. 17) and has a face 250 mm high by 100mm wide. The arced surface 208 could be provided as a flat surface, butan arced surface may allow for: better illumination uniformity, uniformtile sizes, a smaller sized illuminator 196 for packaging constraints,while providing the same effective illumination area capability. In thisexample, the illuminator 196 is a Lambertian emitter wherein the lightemitter has approximately the same intensity in all directions; however,the present disclosure is not so limited. The illuminator 196 isarranged so that, from the perspective of the camera 198, emitted lightrays are specularly reflected from the tear film of the patient's eye192 and undergo constructive and destructive interference in the lipidlayer and layers beneath the lipid layer. In this embodiment, theilluminator 196 is comprised of high efficiency, white light emittingdiodes (LEDs) 210 (see FIGS. 17 and 18) mounted on a printed circuitboard (PCB) 212 (FIG. 18), wherein each LED 210 or each grouping of LEDsis independently addressable by the control system to be turned on andoff, which will be used when providing a tiled illumination approach ofthe patient's tear film. Supporting circuitry (not shown) may beincluded to control operation of the LEDs 210, and to automatically shutoff the LEDs 210 when the OSI device 170 is not in use. Each LED 210 hasa 120 degree (“Lambertian”) forward projection angle, a 1350 mcd maximumintensity, manufactured by LEDtronics. Other light sources other thanLEDs are also possible, including but not limited to lasers,incandescent light, and organic LEDs (OLEDs), as examples. Further, thelight source is not required to be a Lambertian emitter. For example,the light emitted from the light source may be collimated.

As illustrated in FIG. 19, the PCB 212 is placed inside an illuminatorhousing 214. The illuminator housing 214 is comprised of two side panels216A, 216B that are disposed on opposite sides of the arced surfaced 208when held by base and top panels 218, 220, and also includes a rearpanel 222. The arced surface 208 is comprised of a diffuser 209 todiffuse the light emitted by the LEDs 210. The diffuser 208 can beselected to minimize intensity reduction, while providing sufficientscattering to make the illumination uniform light wave fall off on thelight emitted by the outside LEDs 210. The diffuser 209, PCB 212, andrear panel 222 are flexible and fit within grooves 223 located in thetop and base panels 220, 218, and grooves 224 located in the side panels216A, 216B. The illuminator housing 214 is snapped together and the sidepanels 216A, 216B are then screwed to the top and base panels 220, 218.

The diffuser 209 may also be comprised of more than one diffuser panelto improve uniformity in the light emitted from the illuminator 196. Theside panels 216A, 216B and the base and top panels 218, 220 form bafflesaround the PCB 212 and the LEDs 210. The inside of these surfaces maycontain a reflective film (e.g., 3M ESR film) to assist in theuniformity of light emitted by the LEDs 210. The reflective film mayassist in providing a uniform light intensity over an entire area orregion of interest on a patient's tear film. This may be particularly anissue on the outer edges of the illumination pattern. If a tiledapproach is employed to illuminate a patient's tear film, whereby only asubset of the LEDs 210 within baffle partitions in the illuminator 196are turned on at one time, additional edges will be formed as opposed toa single outer edge if all LEDs 210 are turned on with no tile baffles.The baffle partitions are used to delineate individual tiles and formsharp illumination interaction definition between tiles. The fall off oflight intensity at the outer edges of the illumination interaction or attile partition edges may be controlled to be between approximately threepercent (3%) and seven percent (7%). The diffuser 209 should also besufficiently tightly held to the edges and to the tile baffles in theilluminator housing 214 to prevent or reduce shadows on in theillumination pattern.

Providing individually controllable LEDs 210 in the illuminator 196facilitates providing the tiled pattern illumination previouslydescribed. In this manner, certain groupings of LEDs 210 can becontrolled to be turned on and off to provide a desired tiledillumination of the patient's tear film. FIGS. 20-24 show severalexemplary arrangements of organizing the control of the LEDs 210 intogroupings to provide tiled illumination of a tear film by theilluminator 196 in the OSI device 170. In FIG. 20, the LEDs 210 in theilluminator 196 are divided up into two groups (labeled 1-2) of tiles230 each having a 4×6 array of LEDs 210. In this manner, the PCB 212contains two hundred eighty-eight (288) LEDs 210. The groups areprovided ideally to provide uniform diffuse illumination from theilluminator 196 to capture background signal in the form of diffuseillumination from the illuminator 196 in images of the patient's tearfilm, as previously described. First, the LEDs 210 in the tiles 230provided in group 1 are illuminated in a first mode and a first image ofthe patient's tear film is captured. Then, group 2 is illuminated in asecond mode and a second image is captured. This process can be repeatedalternating lighting modes between groups 1 and 2 to obtain a time-basedsequence of images. The first and second images can then be combined toeliminate or reduce background signal in the interference signalrepresenting the specularly reflected light from the tear film, aspreviously discussed. For example, in order to maintain an overall framerate of thirty (30) fps, the video camera 198 would have to operate inat least 60 fps (30 fps×2 groupings).

Other groups are also possible. FIG. 21 provides four groupings (labeled1-4), with each group perhaps having a 4×6 array of LEDs 210. The LEDs210 in each group are illuminated one at a time in sequence (i.e., group1, 2, 3, 4, 1, etc.) and an image is taken of the patient's tear film,with all images composed together to provide an illuminated, backgroundsignal reduced or eliminated, image of the patient's tear film. FIG. 22also provides four groupings (labeled 1-4), with each group having anarray of LEDs 210. In order to maintain an overall frame rate of fifteen(15) fps, the video camera 198 would have to operate in at least 60 fps(15 fps×4 groupings). The groupings arranged so each group provides, assimilar as possible, the same average illumination geometry to thesubject's eye.

FIG. 23 provides twelve groupings (labeled 1-12), with each group alsohaving an array of LEDs 210. In order to maintain an overall frame rateof fifteen (15) fps, the video camera 198 would have to operate at 180fps (15 fps×12 groupings). A high-speed complementary metal oxide (CMOS)camera may be employed as opposed to a CCD camera to achieve this framerate. FIG. 24 also provides twelve groupings (labeled 1-12), with eachgroup having a 3×4 array of LEDs 210. (Higher number of groups providesthe advantage of lowering the background image level due to theilluminator relative to the specular image, thus improving the abilityto remove the induced background. Working against the advantage, highernumbers of tile groups can make it more difficult to produce the sameaverage illumination geometry for all tile modes. Fortunately, withenough tile groups, we may be able to ignore the background contributionfrom the illuminator light entirely, but the ambient and stray light mayneed subtraction by some means. In the limit, increasing the number ofgroups begins to approach a point to point scanning system.)

System Level

Now that the imaging and illumination functions of the OSI device 170have been described, FIG. 25A illustrates a system level diagramillustrating more detail regarding the control system and other internalcomponents of the OSI device 170 provided inside the housing 172according to one embodiment to capture images of a patient's tear filmand process those images. As illustrated therein, a control system 240is provided that provides the overall control of the OSI device 170. Thecontrol system 240 may be provided by any microprocessor-based orcomputer system. The control system 240 illustrated in FIG. 25A isprovided in a system-level diagram and does not necessarily imply aspecific hardware organization and/or structure. As illustrated therein,the control system 240 contains several systems. A camera settingssystem 242 may be provided that accepts camera settings from a clinicianuser. Exemplary camera settings 244 are illustrated, but may be any typeaccording to the type and model of camera provided in the OSI device 170as is well understood by one of ordinary skill in the art.

The camera settings 244 may be provided to (The Imaging Source) cameradrivers 246, which may then be loaded into the video camera 198 uponinitialization of the OSI device 170 for controlling the settings of thevideo camera 198. The settings and drivers may be provided to a buffer248 located inside the video camera 198 to store the settings forcontrolling a CCD 250 for capturing ocular image information from a lens252. Ocular images captured by the lens 252 and the CCD 250 are providedto a de-Bayering function 254 which contains an algorithm forpost-processing of raw data from the CCD 250 as is well known. Theocular images are then provided to a video acquisition system 256 in thecontrol system 240 and stored in memory, such as random access memory(RAM) 258. The stored ocular images or signal representations can thenbe provided to a pre-processing system 260 and a post-processing system262 to manipulate the ocular images to obtain the interferenceinteractions of the specularly reflected light from the tear film andanalyze the information to determine characteristics of the tear film.Pre-processing settings 264 and post-processing settings 266 can beprovided to the pre-processing system 260 and post-processing system262, respectively, to control these functions. These settings 264, 266will be described in more detail below. The post-processed ocular imagesand information may also be stored in mass storage, such as disk memory268, for later retrieval and viewing on the display 174.

The control system 240 may also contain a visualization system 270 thatprovides the ocular images to the display 174 to be displayed inhuman-perceptible form on the display 174. Before being displayed, theocular images may have to be pre-processed in a pre-processing videofunction 272. For example, if the ocular images are provided by a linearcamera, non-linearity (i.e. gamma correction) may have to be added inorder for the ocular images to be properly displayed on the display 174.Further, contrast and saturation display settings 274, which may becontrolled via the display 174 or a device communicating to the display174, may be provided by a clinician user to control the visualization ofocular images displayed on the display 174. The display 174 is alsoadapted to display analysis result information 276 regarding thepatient's tear film, as will be described in more detail below. Thecontrol system 240 may also contain a user interface system 278 thatdrives a graphical user interface (GUI) utility 280 on the display 174to receive user input 282. The user input 282 can include any of thesettings for the OSI device 170, including the camera settings 244, thepre-processing settings 264, the post-processing settings 266, thedisplay settings 274, the visualization system 270 enablement, and videoacquisition system 256 enablement, labeled 1-6. The GUI utility 280 mayonly be accessible by authorized personnel and used for calibration orsettings that would normally not be changed during normal operation ofthe OSI device 170 once configured and calibrated.

Overall Process Flow

FIG. 25B illustrates an exemplary overall flow process performed by theOSI device 170 for capturing tear film images from a patent and analysisfor TFLT measurement. As illustrated in FIG. 25B, the video camera 198is connected via a USB port 283 to the control system 240 (see FIG. 25A)for control of the video camera 198 and for transferring images of apatient's tear film taken by the video camera 198 back to the controlsystem 240. The control system 240 includes a compatible camera driver246 to provide a transfer interface between the control system 240 andthe video camera 198. Prior to tear film image capture, theconfiguration or camera settings 244 are loaded into the video camera198 over the USB port 283 to prepare the video camera 198 for tear filmimage capture (block 285). Further, an audio video interleaved (AVI)container is created by the control system 240 to store video of tearfilm images to be captured by the video camera 198 (block 286). At thispoint, the video camera 198 and control system 240 are ready to captureimages of a patient's tear film. The control system 240 waits for a usercommand to initiate capture of a patient's tear film (blocks 287, 288).

Autopositioning and Autofocus

Before the control system 240 directs the video camera 198 of the OSIdevice 170 in FIG. 16 to capture images of the patient's tear film, itmay be desired to position and focus the video camera 198 to obtain themost accurate images of the patient's tear film possible for moreaccurate analysis. Positioning the video camera 198 involves positioningthe lens of the video camera 198 in the Y-axis and Z-axis directions, asshown in FIG. 16, to be in the desired alignment with the patient's eye192 and tear film to capture an image in a region of interest of thepatient's tear film. As previously discussed above, it may be desired toposition the video camera 198 to capture specularly reflected light froma portion of the tear film that is outside of the pupil area of thepatient's eye 192. Focusing the video camera 198 means changing thefocal length of the lens of the video camera 198 of the OSI device 170in the X-axis directions, as shown in FIG. 16. Changing the focus of thevideo camera 198 changes the point of convergence of the specularlyreflected light returned from the tear film of the patient's eye 192.Ideally, for a non-distorted image of the tear film of the patient's eye192, the focal length should be set for the specularly reflected lightreturned from the tear film of the patient's eye 192 to converge at animaging plane of the video camera 198.

The technician can position the video camera 198 in alignment with thepatient's eye and tear film to be imaged. However, this introduces humanerror and/or involves trial and error by the technician, which may betime consuming. Further, as the OSI device 170 is used to imagedifferent eyes of the same patient, or a new patient, the video camera198 may need to be re-positioned each time. Thus, in embodimentsdisclosed herein, the video camera 198 can be autopositioned by the OSIdevice 170. In this regard, the control system 240 in FIG. 25A can beprogrammed to autoposition the video camera 198 when desired. Forexample, it may be desired for the control system 240 to be programmedto autoposition the video camera 198 prior to step 287 in FIG. 25B,where the video camera 198 and supporting components for storing imagesof the patient's eye 192 are being configured and initialized.

In this regard, as shown in FIG. 26, the control system 240 can instructthe video camera 198 to take a first image of the patient's eye 192 todetect the pupil portion of the patient's eye in the image (block 1000).For example, any technique to detect the pupil portion of patient's eye192 in the image may be used. For example, the control system 240 may beconfigured to detect darker colored regions in the image to detect thelocation of the pupil. Next, the control system 240 determines if thepupil of the patient's eye 192 is at a home position in the image (block1002). For example, the home position could be the center of the image.The home position may be represented in the OSI device 170 as a X-Ycoordinate or pixel coordinate about the standard image size produced bythe video camera 198. The home position may be another location in theimage, but the home position is the position in which it is desired forthe image of the patient's pupil to be located within the image. If thepatient's pupil is located in the home position in the captured image,the video camera 198 is deemed to already be positioned properly forcapturing subsequent images of the patient's eye 192 and tear film forprocessing (block 1004).

However, if the patient's pupil is not located in the home position, thecontrol system 240 can reposition the video camera 198 until thepatient's pupil is located in the home position of an image taken by thevideo camera 198. In this regard, if the pupil of the patient's eye 192is not located in the home position of the image, the control system 240can adjust the position of the video camera 198 in the Y-axis andZ-axis, as illustrated in FIG. 16, to provide for the pupil of thepatient's eye 192 to be located in the home position of the capturedimage of the patient's eye 192 (block 1006). For example, the controlsystem 240 may not need to take a second image of the patient's eye 192to autoposition the video camera 198 if the control system 240 is ableto correlate the distance between the location of the pupil and the homeposition into a positional movement of the video camera 198.

As discussed above, it may also be desired to provide for the videocamera 198 in the OSI device 170 to be autofocused, as opposed to atechnician having to manually focus the lens of the video camera 198.Because each patient has different head profiles, the distance between apatient's eye 192 when situated in the OSI device 170 to the lens of thevideo camera 198 may differ. In this regard, FIG. 27 illustrates aflowchart that provides an exemplary process for the OSI device 170providing autofocusing of the video camera 198. In this regard, thecontrol system 240 can instruct the video camera 198 to take a firstimage of the patient's eye 192 to detect the pupil portion of thepatient's eye 192 in the image (block 1010). For example, any techniqueto detect the pupil portion of the patient's eye 192 in the image may beused. For example, the control system 240 may be configured to detectdarker colored regions in the image to detect the location of the pupil.Next, the control system 240 analyzes the captured image to repositionthe video camera 198 to be directed towards a region below the pupil ofthe patient's eye 192 according to the position of the pupil in thefirst image captured (block 1012). This is because in this example, theautofocusing method takes advantage of the discovery that the patient'seyelashes present a high contrast object that can be imaged by the videocamera 198 and detected by the control system 240 in a resulting image,which can be used to analyze the focus of the video camera 198 and toadjust the focus of the video camera 198, if needed. For example, apatient's eyelashes are shown in captured images of a patient's eye 121in FIGS. 11A and 11B, previous discussed above. Note that the eyelashesof the patient's eye 121 therein appear in high contrast. The controlsystem 240 may be configured to reposition the video camera 198 by afixed distance below the pupil with the assumption that each patient'sbottom eyelashes generally will be located within a given distance fromtheir pupil.

Next, with continued reference to FIG. 27, the control system 240adjusts the focus of the video camera 198 to the beginning of its focalrange (block 1014). The control system 240 then increments the focus ofthe video camera 198 to the next focal increment from the current focalsetting (block 1016). The control system 240 controls the video camera198 to capture another image of the patient's ocular tear film with thevideo camera 198 repositioned as discussed above (block 1018). The imageis stored by the control system 240 along with the focal setting for thevideo camera 198 when the image was captured. The control system 240determines if the video camera 198 focus setting is at the end of itsfocal range (block 1020). If not, the control system 240 repeats thesteps in blocks 1016 and 1018 discussed above to capture additionalimages of the patient's eye 192 with the video camera 198 remainingpositioned below the pupil of the patient's eye 192, as discussed above,over the focal distance range of the video camera 198. Once the focalsetting of the video camera 198 can be adjusted through its focal range,with images of the patient's eye 192 at each focal setting captured andstored, the control system 240 can analyze the stored images todetermine how to auto focus the video camera.

In this regard, with continued reference to FIG. 27, the control system240 analyzes each of the storage images taken at different focal lengthsof the video camera 198 to determine which image has the has the highestcontrast ratio (block 1022). The image with the highest contrast ratiois deemed to be the best focal distance between the video camera 198 andthe patient's eye 192. The control system 240 may be programmed withimage processing software, as discussed in more detail below, todetermine the contrast ratio of an image to be used for comparison toother captured images captured under different focal distance settingsfor the video camera 198. The control system 240 can look up the focalsetting that was used for the video camera 198 to capture the imagehaving the highest contrast ratio to be used as the focal setting forthe video camera 198 to be used for capturing subsequent images of thepatient's ocular tear film for analysis. Optionally, the control system240 can compensate for the focal distance setting of the video camera198 that was used to capture the image having the highest contrast ratiofor the final focal distance setting to use to auto focus the videocamera 198. For example, the control system 240 may compensate the focalsetting used to auto focus the video camera 198 based on knowing thatthere is a distance between eyelashes of the patient's eye 192 and theocular tear film of the patient's eye 192 (block 1024) before theautofocus process is completed (block 1026). For example, a distancebetween eyelashes of the patient's eye 192 and the ocular tear film ofthe patient's eye 192 may be assumed to be a given known distance.

With reference back to FIG. 25B, once image capture is initiated (block288), the control system 240 enables image capture to the AVI containerpreviously setup (block 286) for storage of images captured by the videocamera 198 (block 289). The control system 240 controls the video camera198 to capture images of the patient's tear film (block 289) untiltimeout or the user terminates image capture (block 290) and imagecapture halts or ends (block 291). Images captured by the video camera198 and provided to the control system 240 over the USB port 283 arestored by the control system 240 in RAM 268.

The captured images of the patient's ocular tear film can subsequentlybe processed and analyzed to perform TFLT measurement, as described inmore detail below and throughout the remainder of this disclosure. Theprocess in this embodiment involves processing tear film image pairs toperform background subtraction, as previously discussed. For example,image tiling may be performed to provide the tear film image pairs, ifdesired. The processing can include simply displaying the patient's tearfilm or performing TFLT measurement (block 293). If the display optionis selected to allow a technician to visually view the patient's tearfilm, display processing is performed (block 294) which can be thedisplay processing 270 described in more detail below with regard toFIG. 36. For example, the control system 240 can provide a combinationof images of the patient's tear film that show the entire region ofinterest of the tear film on the display 174. The displayed image mayinclude the background signal or may have the background signalsubtracted. If TFLT measurement is desired, the control system 240performs pre-processing of the tear film images for TFLT measurement(block 295), which can be the pre-processing 260 described in moredetail below with regard to FIG. 28. The control system 240 alsoperforms post-processing of the tear film images for TFLT measurement(block 296), which can be the post-processing 262 described in moredetail below with regard to FIG. 38.

Pre-Processing

FIG. 28 illustrates an exemplary pre-processing system 260 forpre-processing ocular tear film images captured by the OSI device 170for eventual analysis and TFLT measurement. In this system, the videocamera 198 has already taken the first and second tiled images of apatient's ocular tear film, as previously illustrated in FIGS. 11A and11B, and provided the images to the video acquisition system 256. Theframes of the first and second images were then loaded into RAM 258 bythe video acquisition system 256. Thereafter, as illustrated in FIG. 28,the control system 240 commands the pre-processing system 260 topre-process the first and second images. An exemplary GUI utility 280 isillustrated in FIG. 29 that may be employed by the control system 240 toallow a clinician to operate the OSI device 170 and controlpre-processing settings 264 and post-processing settings 266, which willbe described later in this application. In this regard, thepre-processing system 260 loads the first and second image frames of theocular tear film from RAM 258 (block 300). The exemplary GUI utility 280in FIG. 29 allows for a stored image file of previously stored videosequence of first and second image frames captured by the video camera198 by entering a file name in the file name field 351. A browse button352 also allows searches of the memory for different video files, whichcan either be buffered by selecting a buffered box 354 or loaded forpre-processing by selecting the load button 356.

If the loaded first and second image frames of the tear film arebuffered, they can be played using display selection buttons 358, whichwill in turn display the images on the display 174. The images can beplayed on the display 174 in a looping fashion, if desired, by selectingthe loop video selection box 360. A show subtracted video selection box370 in the GUI utility 280 allows a clinician to show the resulting,subtracted video images of the tear film on the display 174representative of the resulting signal comprised of the second outputsignal combined or subtracted from the first output signal, or viceversa. Also, by loading the first and second image frames, thepreviously described subtraction technique can be used to removebackground image from the interference signal representing interferenceof the specularly reflected light from the tear film, as previouslydescribed above and illustrated in FIG. 12 as an example. The firstimage is subtracted from the second image to subtract or remove thebackground signal in the portions producing specularly reflected lightin the second image, and vice versa, and then combined to produce aninterference interaction of the specularly reflected light of the entirearea or region of interest of the tear film, as previously illustratedin FIG. 12 (block 302 in FIG. 28). For example, this processing could beperformed using the Matlab® function “cvAbsDiff.”

The subtracted image containing the specularly reflected light from thetear film can also be overlaid on top of the original image capture ofthe tear film to display an image of the entire eye and the subtractedimage in the display 174 by selecting the show overlaid original videoselection box 362 in the GUI utility 280 of FIG. 29. An example of anoverlaid original video to the subtracted image of specularly reflectedlight from the tear film is illustrated in the image 363 of FIG. 30.This overlay is provided so that flashing images of specularly reflectedlight from the tear film are not displayed, which may be unpleasant tovisualize. The image 363 of the tear film illustrated in FIG. 30 wasobtained with a DBK 21AU04 Bayer VGA (640×480) video camera having aPentax VS-LD25 Daitron 25-mm fixed focal length lens with maximumaperture at a working distance of 120 mm and having the followingsettings, as an example:

Gamma=100 (to provide linearity with exposure value)

Exposure= 1/16 second

Frame rate=60 fps

Data Format=BY8

Video Format=−uncompressed, RGB 24-bit AVI

Hue=180 (neutral, no manipulation)

Saturation=128(neutral, no manipulation)

Brightness=0 (neutral, no manipulation)

Gain=260 (minimum available setting in this camera driver)

White balance=B=78; R=20.

Thresholding

Any number of optional pre-processing steps and functions can next beperformed on the resulting combined tear film image(s), which will nowbe described. For example, an optional threshold pre-processing functionmay be applied to the resulting image or each image in a video of imagesof the tear film (e.g., FIG. 12) to eliminate pixels that have asubtraction difference signal below a threshold level (block 304 in FIG.28). Image threshold provides a black and white mask (on/off) that isapplied to the tear film image being processed to assist in removingresidual information that may not be significant enough to be analyzedand/or may contribute to inaccuracies in analysis of the tear film. Thethreshold value used may be provided as part of a threshold valuesetting provided by a clinician as part of the pre-processing settings264, as illustrated in the system diagram of FIG. 25A. For example, theGUI utility 280 in FIG. 29 includes a compute threshold selection box372 that may be selected to perform thresholding, where the thresholdbrightness level can be selected via the threshold value slide 374. Thecombined tear film image of FIG. 12 is copied and converted tograyscale. The grayscale image has a threshold applied according to thethreshold setting to obtain a binary (black/white) image that will beused to mask the combined tear film image of FIG. 12. After the mask isapplied to the combined tear film image of FIG. 12, the new combinedtear film image is stored in RAM 258. The areas of the tear film imagethat do not meet the threshold brightness level are converted to blackas a result of the threshold mask.

FIGS. 31A and 31B illustrate examples of threshold masks for thecombined tear film provided in FIG. 12. FIG. 31A illustrates a thresholdmask 320 for a threshold setting of 70 counts out of a full scale levelof 255 counts. FIG. 31B illustrates a threshold mask 322 for a thresholdsetting of 50. Note that the threshold mask 320 in FIG. 31A containsless portions of the combined tear film image, because the thresholdsetting is higher than for the threshold mask 322 of FIG. 31B. When thethreshold mask according to a threshold setting of 70 is applied to theexemplary combined tear film image of FIG. 12, the resulting tear filmimage is illustrated FIG. 32. Much of the residual subtracted backgroundimage that surrounds the area or region of interest has been maskedaway.

Erode and Dilate

Another optional pre-processing function that may be applied to theresulting image or each image in a video of images of the tear film tocorrect anomalies in the combined tear film image(s) is the erode anddilate functions (block 306 in FIG. 28). The erode function generallyremoves small anomaly artifacts by subtracting objects with a radiussmaller than an erode setting (which is typically in number of pixels)removing perimeter pixels where interference information may not be asdistinct or accurate. The erode function may be selected by a clinicianin the GUI utility 280 (see FIG. 29) by selecting the erode selectionbox 376. If selected, the number of pixels for erode can be provided inan erode pixels text box 378. Dilating generally connects areas that areseparated by spaces smaller than a minimum dilate size setting by addingpixels of the eroded pixel data values to the perimeter of each imageobject remaining after the erode function is applied. The dilatefunction may be selected by a clinician in the GUI utility 280 (see FIG.29) by providing the number of pixels for dilating in a dilate pixelstext box 380. Erode and dilate can be used to remove small regionanomalies in the resulting tear film image prior to analyzing theinterference interactions to reduce or avoid inaccuracies. Theinaccuracies may include those caused by bad pixels of the video camera198 or from dust that may get onto a scanned image, or more commonly,spurious specular reflections such as: tear film meniscus at thejuncture of the eyelids, glossy eyelash glints, wet skin tissue, etc.FIG. 33 illustrates the resulting tear film image of FIG. 32 after erodeand dilate functions have been applied and the resulting tear film imageis stored in RAM 258. As illustrated therein, pixels previously includedin the tear film image that were not in the tear film area or region ofinterest are removed. This prevents data in the image outside the areaor region of interest from affecting the analysis of the resulting tearfilm image(s).

Removing Blinks/Other Anomalies

Another optional pre-processing function that may be applied to theresulting image or each image in a video of images of the tear film tocorrect anomalies in the resulting tear film image is to remove framesfrom the resulting tear film image that include patient blinks orsignificant eye movements (block 308 in FIG. 28). As illustrated in FIG.28, blink detection is shown as being performed after a threshold anderode and dilate functions are performed on the tear film image or videoof images. Alternatively, the blink detection could be performedimmediately after background subtraction, such that if a blink isdetected in a given frame or frames, the image in such frame or framescan be discarded and not pre-processed. Not pre-processing images whereblinks are detected may increase the overall speed of pre-processing.The remove blinks or movement pre-processing may be selectable. Forexample, the GUI utility 280 in FIG. 29 includes a remove blinksselection box 384 to allow a user to control whether blinks and/or eyemovements are removed from a resulting image or frames of the patient'stear film prior to analysis. Blinking of the eyelids covers the oculartear film, and thus does not produce interference signals representingspecularly reflected light from the tear film. If frames containingwhole or partial blinks obscuring the area or region of interest in thepatient's tear film are not removed, it would introduce errors in theanalysis of the interference signals to determine characteristics of theTFLT of the patient's ocular tear film. Further, frames or data withsignificant eye movement between sequential images or frames can beremoved during the detect blink pre-processing function. Large eyemovements could cause inaccuracy in analysis of a patient's tear film orany area of interest when employing subtraction techniques to removebackground signal, because subtraction involves subtracting frame-pairsin an image that closely match spatially. Thus, if there is significanteye movement between first and second images that are to be subtracted,frame pairs may not be closely matched spatially thus inaccuratelyremoving background signal, and possibly removing a portion of theinterference image of specularly reflected light from the tear film.

Different techniques can be used to determine blinks in an ocular tearfilm image and remove the frames as a result. For example, in oneembodiment, the control system 240 directs the pre-processing system 260to review the stored frames of the resulting images of the tear film tomonitor for the presence of an eye pupil using pattern recognition. AHough Circle Transform may be used to detect the presence of the eyepupil in a given image or frame. If the eye pupil is not detected, it isassembled such that the image or frame contains an eye blink and thusshould be removed or ignored during pre-processing from the resultingimage or video of images of the tear film. The resulting image or videoof images can be stored in RAM 258 for subsequent processing and/oranalysis.

In this regard, in one embodiment, detecting eye blinks in an oculartear film image or frame by detecting the pupil and removing desiredblink frames that do not contain an image of the pupil as a result maybe performed as follows. First, ocular tear film frame pairs, onecontaining specularly reflected light and background signal (i.e., frame1), and the other containing background signal (i.e., frame 2) are addedtogether to provide a resultant image (i.e., frame 1+[frame 2−frame 1]).A grayscale is created of the resultant image, for example using a8-bit, 255 value scale. Providing a grayscale of the resultant imageallows enhanced identification of darker pixels as opposed to lighterpixels, to try to identify pixels associated with the pupil, as anon-limiting example. As discussed above, determining that a pupil is inan ocular tear film image is one direct indication of whether the oculartear film frame contains a partial or full eye blink. Thereafter in thisexample, the darkest pixel in resultant grayscale frame is found. Then,all pixels within a given intensity count are found (e.g., within 7).These are the darkest areas of the frame and include the pupil. A binaryresultant frame is then created with resultant grayscale frame totransform the darker pixels to white color. That binary resultant frameis then eroded and dilated (similar to as discussed in other examplesherein for tear film measurement purposes) using a sample disk. Thelarger or largest contiguous pixels having white color is found in theresultant binary frame. A check is next made to make sure that larger orlargest contiguous pixels having white color contains at least a desiredminimum number of pixels (e.g., 3000) and has a desired eccentricity(e.g., 0.8 or lower). If so, this larger or largest contiguous pixelshaving white color is deemed to be the pupil. If previous frame from thecurrent frame was also deemed to contain the pupil by ensuring thecentroid of the larger or largest contiguous pixels did not shift bymore than a designated number of pixels (e.g., 50 pixels), then thecurrent frame is deemed to contain the pupil and is not rejected. If thecurrent frame is not deemed to contain the pupil, the frame can berejected.

In another embodiment, blinks and significant eye movements are detectedusing a histogram sum of the intensity of pixels in a resultingsubtracted image or frame of a first and second image of the tear film.An example of such a histogram 329 is illustrated in FIG. 34. Theresulting or subtracted image can be converted to grayscale (i.e., 255levels) and a histogram generated with the gray levels of the pixels. Inthe histogram 329 of FIG. 34, the x-axis contains gay level ranges, andthe number of pixels falling within each gray level is contained in they-axis. The total of all the histogram 329 bins are summed. In the caseof two identical frames that are subtracted, the histogram sum would bezero. However, even without an eye blink or significant eye movement,two sequentially captured frames of the patient's eye and theinterference signals representing the specularly reflected light fromthe tear film are not identical. However, frame pairs with littlemovement will have a low histogram sum, while frame pairs with greatermovement will yield a larger histogram sum. If the histogram sum isbeyond a pre-determined threshold, an eye blink or large eye movementcan be assumed and the image or frame removed. For example, the GUIutility 280 illustrated in FIG. 29 includes a histogram sum slide bar386 that allows a user to set the threshold histogram sum. The thresholdhistogram sum for determining whether a blink or large eye movementshould be assumed and thus the image removes from analysis of thepatient's tear film can be determined experimentally, or adaptively overthe course of a frame playback, assuming that blinks occur at regularintervals.

An advantage of a histogram sum of intensity method to detect eye blinksor significant eye movements is that the calculations are highlyoptimized as opposed to pixel-by-pixel analysis, thus assisting withreal-time processing capability. Further, there is no need to understandthe image structure of the patient's eye, such as the pupil or the irisdetails. Further, the method can detect both blinks and eye movements.

In this regard, in one embodiment, detecting eye blinks in an oculartear film image or frame based on an intensity method may be performedas follows. First, the ocular tear film frame pairs, one containingspecularly reflected light and background signal (i.e., frame 1), andthe other containing background signal (i.e., frame 2) are subtractedfrom each together to provide a resultant image (i.e., [frame 2−frame1]). A grayscale is created of the resultant image (e.g., 8-bits, 255sample levels). A histogram is then calculated for the resultantgrayscale image by, for example, dividing intensity in the resultantgrayscale image into a desired number of bins (e.g., 64 bins of 4 countseach). The height of the tallest bin is set to a defined level (e.g.,200) and the scale of all other bins adjusted accordingly. All scaledbins are summed and compared to a predefined limit (e.g., 1000). Ifhistogram sum is greater than this predefined limit, the resultant frameis rejected as a frame having a blink.

To remove blink islands, trains or sequences of consecutive non-blinkframes bookended by blink frames can be identified. If a train consistsof three or fewer non-blink frames, those frames can be rejected asblink frames. The centroid of each resultant subtracted frame iscalculated to find the location of each non-blink pixel (e.g., find theaverage location in X-Y coordinates of center of non-blink pixel). Abounding box of each resultant subtracted frame is also calculated. Theaverage centroid location is calculated for all non-blink frames. Theaverage bounding box location is calculated for all non-blink frames. Ifthe centroid for a given frame deviates from the average centroidlocation for all frames by more than a defined number of pixels (e.g.,30) up, down, or temporally (from temple or nose of patient), then thatframe can be rejected as a blink frame. If top, bottom, or temporaledges of bounding box deviate from the average bounding box location bymore than 30 pixels, the frame can be rejected as a blink frame. Theblink island removal process can be repeated labeling blink islands aseither blink or non-blink islands. Optionally, a first number of frames(e.g., 5) after each blink to allow tear film to stabilize beforequantifying lipid layer thickness.

Another alternate technique to detect blinks in the tear film image orvideo of images for possible removal is to calculate a simple averagegray level in an image or video of images. Because the subtracted,resulting images of the tear film subtract background signal, and havebeen processed using a threshold mask, and erode and dilate functionsperformed in this example, the resulting images will have a loweraverage gray level due to black areas present than if a blink ispresent. A blink contains skin color, which will increase the averagegray level of an image containing a blink. A threshold average graylevel setting can be provided. If the average gray level of a particularframe is below the threshold, the frame is ignored from further analysisor removed from the resulting video of frames of the tear film.

Another alternate technique to detect blinks in an image or video ofimages for removal is to calculate the average number of pixels in agiven frame that have a gray level value below a threshold gray levelvalue. If the percentage of pixels in a given frame is below a definedthreshold percentage, this can be an indication that a blink hasoccurred in the frame, or that the frame is otherwise unworthy ofconsideration when analyzing the tear film. Alternatively, a spatialfrequency calculation can be performed on a frame to determine theamount of fine detail in a given frame. If the detail present is below athreshold detail level, this may be an indication of a blink or otherobscurity of the tear film, since skin from the eyelid coming down andbeing captured in a frame will have less detail than the subtractedimage of the tear film. A histogram can be used to record any of theabove-referenced calculations to use in analyzing whether a given frameshould be removed from the final pre-processed resulting image or imagesof the tear film for analysis.

ICC Profiling

Pre-processing of the resulting tear film image(s) may also optionallyinclude applying an International Colour Consortium (ICC) profile to thepre-processed interference images of the tear film (block 310, FIG. 28).FIG. 35 illustrates an optional process of loading an ICC profile intoan ICC profile 331 in the control system 240 (block 330). In thisregard, the GUI utility 280 illustrated in FIG. 29 also includes anapply ICC box 392 that can be selected by a clinician to load the ICCprofile 331. The ICC profile 331 may be stored in memory in the controlsystem 240, including in RAM 258. In this manner, the GUI utility 280 inFIG. 29 also allows for a particular ICC profile 331 to be selected forapplication in the ICC profile file text box 394. The ICC profile 331can be used to adjust color reproduction from scanned images fromcameras or other devices into a standard red-green-blue (RGB) colorspace (among other selectable standard color spaces) defined by the ICCand based on a measurement system defined internationally by theCommission Internationale de l'Eclairage (CIE). Adjusting thepre-processed resulting tear film interference images corrects forvariations in the camera color response and the light source spectrumand allows the images to be compatibly compared with a tear film layerinterference model to measure the thickness of a TFLT, as will bedescribed later in this application. The tear film layers represented inthe tear film layer interference model can be LLTs, ALTs, or both, aswill be described in more detail below.

In this regard, the ICC profile 331 may have been previously loaded tothe OSI device 170 before imaging of a patient's tear film and alsoapplied to a tear film layer interference model when loaded into the OSIdevice 170 independent of imaging operations and flow. As will bediscussed in more detail below, a tear film layer interference model inthe form of a TFLT palette 333 containing color-based valuesrepresenting interference interactions from specularly reflected lightfrom a tear film for various LLTs and ALTs can also be loaded into theOSI device 170 (block 332 in FIG. 38). The tear film layer interferencemodel 333 contains a series of color-based values that are assigned LLTsand/or ALTs based on a theoretical tear film layer interference model tobe compared against the color-based value representations ofinterference interactions in the resulting image(s) of the patient'stear film. When applying the optional ICC profile 331 to the tear filmlayer interference model 333 (block 334 in FIG. 35), the color-basedvalues in both the tear film layer interference model and thecolor-based values representing interference interactions in theresulting image of the tear film are adjusted for a more accuratecomparison between the two to measure LLT and/or ALT.

Brightness

Also as an optional pre-processing step, brightness and red-green-blue(RGB) subtract functions may be applied to the resulting interferencesignals of the patient's tear film before post-processing for analysisand measuring TFLT is performed (blocks 312 and 314 in FIG. 28). Thebrightness may be adjusted pixel-by-pixel by selecting the adjustbrightness selection box 404 according to a corresponding brightnesslevel value provided in a brightness value box 406, as illustrated inthe GUI utility 280 of FIG. 29. When the brightness value box 406 isselected, the brightness of each palette value of the tear filminterference model 333 is also adjusted accordingly.

RGB Subtraction (Normalization)

The RGB subtract function subtracts a DC offset from the interferencesignal in the resulting image(s) of the tear film representing theinterference interactions in the interference signal. An RGB subtractsetting may be provided from the pre-processing settings 264 to apply tothe interference signal in the resulting image of the tear film tonormalize against. As an example, the GUI utility 280 in FIG. 29 allowsan RGB offset to be supplied by a clinician or other technician for usein the RGB subtract function. As illustrated therein, the subtract RGBfunction can be activated by selecting the RGB subtract selection box396. If selected, the individual RGB offsets can be provided in offsetvalue input boxes 398. After pre-processing is performed, if any, on theresulting image, the resulting image can be provided to apost-processing system to measure TLFT (block 316), as discussed laterbelow in this application.

Displaying Images

The resulting images of the tear film may also be displayed on thedisplay 174 of the OSI device 170 for human diagnosis of the patient'socular tear film. The OSI device 170 is configured so that a cliniciancan display and see the raw captured image of the patient's eye 192 bythe video camera 198, the resulting images of the tear film beforepre-processing, or the resulting images of the tear film afterpre-processing. Displaying images of the tear film on the display 174may entail different settings and steps. For example, if the videocamera 198 provides linear images of the patient's tear film, the linearimages must be converted into a non-linear format to be properlydisplayed on the display 174. In this regard, a process that isperformed by the visualization system 270 according to one embodiment isillustrated in FIG. 36.

As illustrated in FIG. 36, the video camera 198 has already taken thefirst and second tiled images of a patient's ocular tear film aspreviously illustrated in FIGS. 11A and 11B, and provided the images tothe video acquisition system 256. The frames of the first and secondimages were then loaded into RAM 258 by the video acquisition system256. Thereafter, as illustrated in FIG. 36, the control system 240commands the visualization system 270 to process the first and secondimages to prepare them for being displayed on the display 174, 338. Inthis regard, the visualization system 270 loads the first and secondimage frames of the ocular tear film from RAM 258 (block 335). Thepreviously described subtraction technique is used to remove backgroundsignal from the interference interactions of the specularly reflectedlight from the tear film, as previously described above and illustratedin FIG. 12. The first image(s) is subtracted from the second image(s) toremove background signal in the illuminated portions of the firstimage(s), and vice versa, and the subtracted images are then combined toproduce an interference interaction of the specularly reflected light ofthe entire area or region of interest of the tear film, as previouslydiscussed and illustrated in FIG. 12 (block 336 in FIG. 36).

Again, for example, this processing could be performed using the Matlab®function “cvAbsDiff.” Before being displayed, the contrast andsaturation levels for the resulting images can be adjusted according tocontrast and saturation settings provided by a clinician via the userinterface system 278 and/or programmed into the visualization system 270(block 337). For example, the GUI utility 280 in FIG. 29 provides anapply contrast button 364 and a contrast setting slide 366 to allow theclinician to set the contrast setting in the display settings 274 fordisplay of images on the display 174. The GUI utility 280 also providesan apply saturation button 368 and a saturation setting slide 369 toallow a clinician to set the saturation setting in the display settings274 for the display of images on the display 174. The images can then beprovided by the visualization system 270 to the display 174 fordisplaying (block 338 in FIG. 36). Also, any of the resulting imagesafter pre-processing steps in the pre-processing system 260 can beprovided to the display 174 for processing.

FIGS. 37A-37C illustrate examples of different tear film images that aredisplayed on the display 174 of the OSI device 170. FIG. 37A illustratesa first image 339 of the patient's tear film showing the tiled patterncaptured by the video camera 198. This image is the same image asillustrated in FIG. 11A and previously described above, but processedfrom a linear output from the video camera 198 to be properly displayedon the display 174. FIG. 37B illustrates a second image 340 of thepatient's tear film illustrated in FIG. 11B and previously describedabove. FIG. 37C illustrates a resulting “overlaid” image 341 of thefirst and second images 339, 340 of the patient's tear film and toprovide interference interactions of the specularly reflected light fromthe tear film over the entire area or region of interest. This is thesame image as illustrated in FIG. 12 and previously described above.

In this example, the original number of frames of the patient's tearfilm captured can be reduced by half due to the combination of the firstand second tiled pattern image(s). Further, if frames in the subtractedimage frames capture blinks or erratic movements, and these frames areeliminated in pre-processing, a further reduction in frames will occurduring pre-processing from the number of images raw captured in imagesof the patient's tear film. Although these frames are eliminated frombeing further processed, they can be retained for visualizationrendering a realistic and natural video playback. Further, by applying athresholding function and erode and dilating functions, the number ofnon-black pixels which contain TLFT interference information issubstantially reduced as well. Thus, the amount of pixel informationthat is processed by the post-processing system 262 is reduced, and maybe on the order of 70% less information to process than the raw imagecapture information, thereby pre-filtering for the desired interferenceROI and reducing or elimination potentially erroneous information aswell as allowing for faster analysis due to the reduction ininformation.

At this point, the resulting images of the tear film have beenpre-processed by the pre-processing system 260 according to whateverpre-processing settings 264 and pre-processing steps have been selectedor implemented by the control system 240. The resulting images of thetear film are ready to be processed for analyzing and determining TFLT.In this example, this is performed by the post-processing system 262 inFIG. 25A and is based on the post-processing settings 266 alsoillustrated therein. An embodiment of the post-processing performed bythe post-processing system 262 is illustrated in the flowchart of FIG.38.

Tear Film Interference Models

As illustrated in FIG. 38, pre-processed images 343 of the resultingimages of the tear film are retrieved from RAM 258 where they werepreviously stored by the pre-processing system 260. Before discussingthe particular embodiment of the post-processing system 262 in FIG. 38,in general, to measure TFLT, the RGB color-based values of the pixels inthe resulting images of the tear film are compared against color-basedvalues stored in a tear film interference model that has been previouslyloaded into the OSI device 170 (see FIG. 35. The tear film interferencemodel may be stored as a TFLT palette 333 containing RGB valuesrepresenting interference colors for given LLTs and/or ALTs. The TFLTpalette contains interference color-based values that represent TFLTsbased on a theoretical tear film interference model in this embodiment.Depending on the TFLT palette provided, the interference color-basedvalues represented therein may represent LLTs, ALTs, or both. Anestimation of TFLT for each ROI pixel is based on this comparison. Thisestimate of TFLT is then provided to the clinician via the display 174and/or recorded in memory to assist in diagnosing DES.

Before discussing embodiments of how the TFLTs are estimated from thepre-processed resulting image colored interference interactionsresulting from specularly reflected light from the tear film, tear filminterference modeling is first discussed. Tear film interferencemodeling can be used to determine an interference color-based value fora given TFLT to measure TFLT, which can include both LLT and/or ALT.

Although the interference signals representing specularly reflectedlight from the tear film are influenced by all layers in the tear film,the analysis of interference interactions due to the specularlyreflected light can be analyzed under a 2-wave tear film model (i.e.,two reflections) to measure LLT. A 2-wave tear film model is based on afirst light wave(s) specularly reflecting from the air-to-lipid layertransition of a tear film and a second light wave specularly reflectingfrom the lipid layer-to-aqueous layer transition of the tear film. Inthe 2-wave model, the aqueous layer is effective ignored and treated tobe of infinite thickness. To measure LLT using a 2-wave model, a 2-wavetear film model was developed wherein the light source and lipid layersof varying thicknesses were modeled mathematically. To model thetear-film interference portion, commercially available software, such asthat available by FilmStar and Zemax as examples, allows imagesimulation of thin films for modeling. Relevant effects that can beconsidered in the simulation include refraction, reflection, phasedifference, polarization, angle of incidence, and refractive indexwavelength dispersion. For example, a lipid layer could be modeled ashaving an index of refraction of 1.48 or as a fused silica substrate(SiO₂) having a 1.46 index of refraction. A back material, such asMagnesium Flouride (MgF₂) having an index of refraction of 1.38 may beused to provide a 2-wave model of air/SiO₂/MgF₂ (1.0/1.46/1.38). Toobtain the most accurate modeling results, the model can include therefractive index and wavelength dispersion values of biological lipidmaterial and biological aqueous material, found from the literature,thus to provide a precise two-wave model of air/lipid/aqueous layers.Thus, a 2-wave tear film interference model allows measurement of LLTregardless of ALT.

Simulations can be mathematically performed by varying the LLT between10 to 300 nm. As a second step, the RGB color-based values of theresulting interference signals from the modeled light source causing themodeled lipid layer to specularly reflected light and received by themodeled camera were determined for each of the modeled LLT. These RGBcolor-based values representing interference interactions in specularlyreflected light from the modeled tear film were used to form a 2-wavemodel LLT palette, wherein each RGB color-based value is assigned adifferent LLT. The resulting subtracted image of the first and secondimages from the patient's tear film containing interference signalsrepresenting specularly reflected light are compared to the RGBcolor-based values in the 2-wave model LLT palette to measure LLT.

In another embodiment, a 3-wave tear film interference model may beemployed to estimate LLT. A 3-wave tear film interference model does notassume that the aqueous layer is infinite in thickness. In an actualpatient's tear film, the aqueous layer is not infinite. The 3-wave tearfilm interference model is based on both the first and second reflectedlight waves of the 2-wave model and additionally light wave(s)specularly reflecting from the aqueous-to-mucin layer and/or corneatransitions. Thus, a 3-wave tear film interference model recognizes thecontribution of specularly reflected light from the aqueous-to-mucinlayer and/or cornea transition that the 2-wave tear film interferencemodel does not. To estimate LLT using a 3-wave tear film interferencemodel, a 3-wave tear film model was previously constructed wherein thelight source and a tear film of varying lipid and aqueous layerthicknesses were mathematically modeled. For example, a lipid layercould be mathematically modeled as a material having an index ofrefraction of 1.48 or as fused silica substrate (SiO₂), which has a 1.46index of refraction. Different thicknesses of the lipid layer can besimulated. A fixed thickness aqueous layer (e.g., >=2 μm) could bemathematically modeled as Magnesium Flouride (MgF₂) having an index ofrefraction of 1.38. A biological cornea could be mathematically modeledas fused silica with no dispersion, thereby resulting in a 3-wave modelof air/SiO₂/MgF₂/SiO₂ (i.e., 1.0/1.46/1.38/1.46 with no dispersion). Asbefore, accurate results are obtained if the model can include therefractive index and wavelength dispersion values of biological lipidmaterial, biological aqueous material, and cornea tissue, found from theliterature, thus to provide a precise two-wave model ofair/lipid/aqueous/cornea layers. The resulting interference interactionsof specularly reflected light from the various LLT values and with afixed ALT value are recorded in the model and, when combined withmodeling of the light source and the camera, will be used to compareagainst interference from specularly reflected light from an actual tearfilm to measure LLT and/or ALT.

In another embodiment of the OSI device 170 and the post-processingsystem 262 in particular, a 3-wave tear film interference model isemployed to estimate both LLT and ALT. In this regard, instead ofproviding either a 2-wave theoretical tear film interference model thatassumes an infinite aqueous layer thickness or a 3-wave model thatassumes a fixed or minimum aqueous layer thickness (e.g., >2 μm), a3-wave theoretical tear film interference model is developed thatprovides variances in both LLT and ALT in the mathematical model of thetear film. Again, the lipid layer in the tear film model could bemodeled mathematically as a material having an index of refraction of1.48 or as fused silica substrate (SiO₂) having a 1.46 index ofrefraction. The aqueous layer could be modeled mathematically asMagnesium Flouride (MgF₂) having an index of refraction of 1.38. Abiological cornea could be modeled as fused silica with no dispersion,thereby resulting in a 3-wave model of air/SiO₂/MgF₂/SiO₂ (nodispersion). Once again, the most accurate results are obtained if themodel can include the refractive index and wavelength dispersion valuesof biological lipid material, biological aqueous material, and corneatissue, found from the literature, thus to provide a precise two-wavemodel of air/lipid/aqueous/cornea layers. Thus, a two-dimensional (2D)TFLT palette 430 (FIG. 39A) is produced for analysis of interferenceinteractions from specularly reflected light from the tear film. Onedimension of the TFLT palette 430 represents a range of RGB color-basedvalues each representing a given theoretical LLT calculated bymathematically modeling the light source and the camera and calculatingthe interference interactions from specularly reflected light from thetear film model for each variation in LLT 434 in the tear filminterference model. A second dimension of the TFLT palette 430represents ALT also calculated by mathematically modeling the lightsource and the camera and calculating the interference interactions fromspecularly reflected light from the tear film interference model foreach variation in ALT 432 at each LLT value 434 in the tear filminterference model.

Post-Processing/TFLT Measurement

To measure TFLT, a spectral analysis of the resulting interferencesignal or image is performed during post-processing to calculate a TFLT.In one embodiment, the spectral analysis is performed by performing alook-up in a tear film interference model to compare one or moreinterference interactions present in the resulting interference signalrepresenting specularly reflected light from the tear film to the RGBcolor-based values in the tear film interference model. In this regard,FIGS. 39A and 39B illustrate two examples of palette models for use inpost-processing of the resulting image having interference interactionsfrom specularly reflected light from the tear film using a 3-wavetheoretical tear film interference model developed using a 3-wavetheoretical tear film model. In general, an RGB numerical value colorscheme is employed in this embodiment, wherein the RGB value of a givenpixel from a resulting pre-processed tear film image of a patient iscompared to RGB values in the 3-wave tear film interference modelrepresenting color-based values for various LLTs and ALTs in a 3-wavemodeled theoretical tear film. The closest matching RGB color is used todetermine the LLT and/or ALT for each pixel in the resulting signal orimage. All pixels for a given resulting frame containing the resultinginterference signal are analyzed in the same manner on a pixel-by-pixelbasis. A histogram of the LLT and ALT occurrences is then developed forall pixels for all frames and the average LLT and ALT determined fromthe histogram (block 348 in FIG. 38).

FIG. 39A illustrates an exemplary TFLT palette 430 in the form of colorsrepresenting the included RGB color-based values representinginterference of specularly reflected light from a 3-wave theoreticaltear film model used to compared colors from the resulting image of thepatient's tear film to estimate LLT and ALT. FIG. 39B illustrates analternative example of a TFLT palette 430′ in the form of colorsrepresenting the included RGB color-based values representinginterference of specularly reflected light from a 3-wave theoreticaltear film model used to compare colors from the resulting image of thepatient's tear film to estimate LLT and ALT. As illustrated in FIG. 39A,the TFLT palette 430 contains a plurality of hue colors arranged in aseries of rows 432 and columns 434. In this example, there are 144 colorhue entries in the palette 430, with nine (9) different ALTs and sixteen(16) different LLTs in the illustrated TFLT palette 430, althoughanother embodiment includes thirty (30) different LLTs. Providing anynumber of LLT and TFLT increments is theoretically possible. The columns434 in the TFLT palette 430 contain a series of LLTs in ascending orderof thickness from left to right. The rows 432 in the TFLT palette 430contain a series of ALTs in ascending order of thickness from top tobottom. The sixteen (16) LLT increments provided in the columns 434 inthe TFLT palette 430 are 25, 50, 75, 80, 90, 100, 113, 125, 138, 150,163, 175, 180, 190, 200, and 225 nanometers (nm). The nine (9) ALTincrements provided in the rows 432 in the TFLT palette 430 are 0.25,0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 3.0 and 6.0 μm. As another example, asillustrated in FIG. 39B, the LLTs in the columns 434′ in the TFLTpalette 430′ are provided in increments of 10 nm between 0 nm and 160nm. The nine (9) ALT increments provided in the rows 432′ in the TFLTpalette 430 are 0.3, 0.5, 0.8, 1.0, 1.3, 1.5, 1.8, 2.0 and 5.0 μm.

As part of a per pixel LLT analysis 344 provided in the post-processingsystem 262 in FIG. 38, for each pixel in each of the pre-processedresulting images of the area or region of interest in the tear film, aclosest match determination is made between the RGB color of the pixelto the nearest RGB color in the TFLT palette 430 (block 345 in FIG. 38).The ALTs and LLTs for that pixel are determined by the corresponding ALTthickness in the y-axis of the TFLT palette 430, and the correspondingLLT thickness in the x-axis of the TFLT palette 430. As illustrated inFIG. 39, the TFLT palette 430 colors are actually represented by RGBvalues. The pixels in each of the pre-processed resulting images of thetear film are also converted and stored as RGB values, although anyother color representation can be used as desired, as long as thepalette and the image pixel data use the same representational colorspace. FIG. 40 illustrates the TFLT palette 430 in color pattern formwith normalization applied to each red-green-blue (RGB) color-basedvalue individually. Normalizing a TFLT palette is optional. The TFLTpalette 430 in FIG. 40 is displayed using brightness control (i.e.,normalization, as previously described) and without the RGB valuesincluded, which may be more visually pleasing to a clinician ifdisplayed on the display 174. The GUI utility 280 allows selection ofdifferent palettes by selecting a file in the palette file drop down402, as illustrated in FIG. 29, each palette being specific to thechoice of 2-wave vs. 3-wave mode, the chosen source's spectrum, and thechosen camera's RGB spectral responses. To determine the closest pixelcolor in the TFLT palette 430, a Euclidean distance color differenceequation is employed to calculate the distance in color between the RGBvalue of a pixel from the pre-processed resulting image of the patient'stear film and RGB values in the TFLT palette 430 as follows below,although the present disclosure is not so limited:

Diff.=√((Rpixel−Rpalette)²+(Gpixel−Gpalette)²+(Bpixel−Bpalette)²)

Thus, the color difference is calculated for all palette entries in theTFLT palette 430. The corresponding LLT and ALT values are determinedfrom the color hue in the TFLT palette 430 having the least differencefrom each pixel in each frame of the pre-processed resulting images ofthe tear film. The results can be stored in RAM 258 or any otherconvenient storage medium. To prevent pixels without a close match to acolor in the TFLT palette 430 from being included in a processed resultof LLT and ALT, a setting can be made to discard pixels from the resultsif the distance between the color of a given pixel is not within theentered acceptable distance of a color-based value in the TFLT palette430 (block 346 in FIG. 38). The GUI utility 280 in FIG. 29 illustratesthis setting such as would be the case if made available to a technicianor clinician. A distance range input box 408 is provided to allow themaximum distance value to be provided for a pixel in a tear film imageto be included in LLT and ALT results. Alternatively, all pixels can beincluded in the LLT and ALT results by selecting the ignore distanceselection box 410 in the GUI utility 280 of FIG. 29.

Each LLT and ALT determined for each pixel from a comparison in the TFLTpalette 430 via the closest matching color that is within a givendistance (if that post-proces sing setting 266 is set) or for all LLTand ALT determined values are then used to build a TFLT histogram. TheTFLT histogram is used to determine a weighted average of the LLT andALT values for each pixel in the resulting image(s) of the patient'stear film to provide an overall estimate of the patient's LLT and ALT.FIG. 41 illustrates an example of such a TFLT histogram 460. This TFLThistogram 440 may be displayed as a result of the shown LLT histogramselection box 400 being selected in the GUI utility 280 of FIG. 29. Asillustrated therein, for each pixel within an acceptable distance, theTFLT histogram 440 is built in a stacked fashion with determined ALTvalues 444 stacked for each determined LLT value 442 (block 349 in FIG.38). Thus, the TFLT histogram 440 represents LLT and ALT values for eachpixel. A horizontal line separates each stacked ALT value 444 withineach LLT bar.

One convenient way to determine the final LLT and ALT estimates is witha simple weighted average of the LLT and ALT values 442, 444 in the TFLThistogram 440. In the example of the TFLT histogram 440 in FIG. 41, theaverage LLT value 446 was determined to be 90.9 nm. The number ofsamples 448 (i.e., pixels) included in the TFLT histogram 440 was31,119. The frame number 450 indicates which frame of the resultingvideo image is being processed, since the TFLT histogram 440 representsa single frame result, or the first of a frame pair in the case ofbackground subtraction. The maximum distance 452 between the color ofany given pixel among the 31,119 pixels and a color in the TFLT palette430 was 19.9, 20 may have been the set limit (Maximum Acceptable PaletteDistance) for inclusion of any matches. The average distance 454 betweenthe color of each of the 31,119 pixels and its matching color in theTFLT palette 430 was 7.8. The maximum distance 452 and average distance454 values provide an indication of how well the color-based values ofthe pixels in the interference signal of the specularly reflected lightfrom the patient's tear film match the color-based values in the TFLTpalette 430. The smaller the distance, the closer the matches. The TFLThistogram 440 can be displayed on the display 174 to allow a clinicianto review this information graphically as well as numerically. If eitherthe maximum distance 452 or average distance 454 values are too high,this may be an indication that the measured LLT and ALT values may beinaccurate, or that the image normalization is not of the correct value.Further imaging of the patient's eye and tear film, or systemrecalibration can be performed to attempt to improve the results. Also,a histogram 456 of the LLT distances 458 between the pixels and thecolors in the TFLT palette 430 can be displayed as illustrated in FIG.42 to show the distribution of the distance differences to furtherassist a clinician in judgment of the results.

Other results can be displayed on the display 174 of the OSI device 170that may be used by a physician or technician to judge the LLT and/orALT measurement results. For example, FIG. 43 illustrates a thresholdwindow 424 illustrating a (inverse) threshold mask 426 that was usedduring pre-processing of the tear film images. In this example, thethreshold window 424 was generated as a result of the show thresholdwindow selection box 382 being selected in the GUI utility 280 of FIG.29. This may be used by a clinician to humanly evaluate whether thethreshold mask looks abnormal. If so, this may have caused the LLT andALT estimates to be inaccurate and may cause the clinician to discardthe results and image the patient's tear film again. The maximumdistance between the color of any given pixel among the 31,119 pixelsand a color in the palette 430 was 19.9 in this example.

FIG. 44 illustrates another histogram that may be displayed on thedisplay 174 and may be useful to a clinician. As illustrated therein, athree-dimensional (3D) histogram plot 460 is illustrated. The cliniciancan choose whether the OSI device 170 displays this histogram plot 460by selecting the 3D plot selection box 416 in the GUI utility 280 ofFIG. 29, as an example, or the OSI device 170 may automatically displaythe histogram plot 460. The 3D histogram plot 460 is simply another wayto graphically display the fit of the processed pixels from thepre-processed images of the tear film to the TFLT palette 430. The planedefined by the LLT 462 and ALT 464 axes represents the TFLT palette 430.The axis labeled “Samples” 466 is the number of pixels that match aparticular color in the TFLT palette 430.

FIG. 45 illustrates a result image 428 of the specularly reflected lightfrom a patient's tear film. However, the actual pixel value for a givenarea on the tear film is replaced with the determined closest matchingcolor-based value representation in the TFLT palette 430 to a givenpixel for that pixel location in the resulting image of the patient'stear film (block 347 in FIG. 38). This setting can be selected, forexample, in the GUI utility 280 of FIG. 29. Therein, a “replaceresulting image . . . ” selection box 412 is provided to allow aclinician to choose this option. Visually displaying interferenceinteractions representing the closest matching color-based value to theinterference interactions in the interference signal of the specularlyreflected light from a patient's tear film in this manner may be helpfulto determine how closely the tear film interference model matches theactual color-based value representing the resulting image (or pixels inthe image).

Ambiguities can arise when calculating the nearest distance between anRGB value of a pixel from a tear film image and RGB values in a TFLTpalette, such as TFLT palettes 430 and 430′ in FIGS. 39A and 39B asexamples. This is because when the theoretical LLT of the TFLT paletteis plotted in RGB space for a given ALT in three-dimensional (3D) space,the TFLT palette 469 is a locus that resembles a pretzel like curve, asillustrated with a 2-D representation in the exemplary TFLT palettelocus 470 in FIG. 46. Ambiguities can arise when a tear film image RGBpixel value has close matches to the TFLT palette locus 470 atsignificantly different LLT levels. For example, as illustrated in theTFLT palette locus 470 in FIG. 46, there are three (3) areas of closeintersection 472, 474, 476 between RGB values in the TFLT palette locus470 even though these areas of close intersection 472, 474, 476represent substantially different LLTs on the TFLT palette locus 470.This is due to the cyclical phenomenon caused by increasing orders ofoptical wave interference, and in particular, first order versus secondorder interference for the LLT range in the tear films. Thus, if an RGBvalue of a tear film image pixel is sufficiently close to two differentLLT points in the TFLT palette locus 470, the closest RGB match may bedifficult to match. The closest RGB match may be to an incorrect LLT inthe TFLT palette locus 470 due to error in the camera and translation ofreceived light to RGB values. Thus, it may be desired to provide furtherprocessing when determining the closest RGB value in the TFLT palettelocus 470 to RGB values of tear film image pixel values when measuringTFLT.

In this regard, there are several possibilities that can be employed toavoid ambiguous RGB matches in a TFLT palette. For example, the maximumLLT values in a TFLT palette may be limited. For example, the TFLTpalette locus 470 in FIG. 46 includes LLTs between 10 nm and 300 nm. Ifthe TFLT palette locus 470 was limited in LLT range, such as 240 nm asillustrated in the TFLT palette locus 478 in FIG. 47, two areas of closeintersection 474 and 476 in the TFLT palette 469 in FIG. 46 are avoidedin the TFLT palette 469 of FIG. 47. This restriction of the LLT rangesmay be acceptable based on clinical experience since most patients donot exhibit tear film colors above the 240 nm range and dry eye symptomsare more problematic at thinner LLTs. In this scenario, the limited TFLTpalette 469 of FIG. 47 would be used as the TFLT palette in thepost-processing system 262 in FIG. 38, as an example.

Even by eliminating two areas of close intersection 474, 476 in the TFLTpalette 469, as illustrated in FIG. 47, the area of close intersection472 still remains in the TFLT palette locus 478. In this embodiment, thearea of close intersection 472 is for LLT values near 20 nm versus 180nm. In these regions, the maximum distance allowed for a valid RGB matchis restricted to a value of about half the distance of the TFLTpalette's 469 nearing ambiguity distance. In this regard, RGB values fortear film pixels with match distances exceeding the specified values canbe further excluded from the TFLT calculation to avoid tear film pixelshaving ambiguous corresponding LLT values for a given RGB value to avoiderror in TFLT measurement as a result.

In this regard, FIG. 48 illustrates the TFLT palette locus 478 in FIG.47, but with a circle of radius R swept along the path of the TFLTpalette locus 478 in a cylinder or pipe 480 of radius R. Radius R is theacceptable distance to palette (ADP), which can be configured in thecontrol system 240. When visualized as a swept volume inside thecylinder or pipe 480, RGB values of tear film image pixels that fallwithin those intersecting volumes may be considered ambiguous and thusnot used in calculating TFLT, including the average TFLT. The smallerthe ADP is set, the more poorly matching tear film image pixels that maybe excluded in TFLT measurement, but less pixels are available for usein calculation of TFLT. The larger the ADP is set, the less tear filmimage pixels that may be excluded in TFLT measurement, but it is morepossible that incorrect LLTs are included in the TFLT measurement. TheADP can be set to any value desired. Thus, the ADP acts effectively as afilter to filter out RGB values for tear film images that are deemed apoor match and those that may be ambiguous according to the ADP setting.This filtering can be included in the post-processing system 262 in FIG.38, as an example, and in step 346 therein, as an example.

As will be described below by example, there are other additionalpost-processing procedures that can be performed on images captured bythe video camera 198 in the OSI device 170 in FIG. 16 representinginterference interactions of specularly reflected light from a patient'stear film results to assist in analysis of the patient's tear film. Forexample, FIG. 49A is a flowchart illustrating an exemplary process forimaging an ocular tear film and performing the pre-processing andpost-processing processes of FIGS. 28 and 38, respectively, andperforming additional filtering to prepare an image of the ocular tearfilm for additional processing. As previously discussed, an image orvideo of a patient's ocular tear film may be captured by the videocamera 198 in the OSI device 170 in FIG. 16 representing interferenceinteractions of specularly reflected light from a patient's ocular tearfilm results to assist in analysis of the patient's ocular tear film(e.g., in block 300 in FIG. 28). As shown in FIG. 49A, the image orvideo of the patient's ocular tear film may be pre-processed, such asfor background subtraction (e.g., in block 302 in FIG. 28) and blinkdetection (e.g., in block 308 in FIG. 28). Thereafter, the TFLT may bemeasured as previously described above (e.g., in block 262 in FIG. 38).Before performing other additional post-processing procedures oncaptured images of a patient's ocular tear film, additional filteringmay be performed. For example, additional spatial filtering (block 1031)and temporal filtering (block 1033) may be performed before performingother additional post-processing procedures on captured images of apatient's ocular tear film (block 1035).

Spatial/Temporal Filtering

In this regard, FIG. 49B is a flowchart illustrating exemplary processesfor spatially and/or temporally filtering of the pre-processed tear filmimage on images captured by the video camera 198 in the OSI device 170in FIG. 16. Spatial and/or temporal filtering can reduce or correcterrant pixels that would show up as noise in the additionalpost-processing of the tear film image. Spatial filtering of a tear filmimage reduces the effect of noise in the tear film image by changing thevalue of pixels in the tear film image based on the intensity ofneighboring pixels. For example, spatial filtering may eliminate errantpixels that are noise and would image as out of place dots or pixels ina tear film image. Temporal filtering of a tear film image reviews thesame pixel or image over time in a series of images of the tear film andprovides an averaging of the pixel value to smooth out errant pixels ina tear film image as a method of performing noise reduction. The pixelaveraging could be weighted unequal between different images of the tearfilm.

With reference to FIG. 49B, the spatial filtering process begins bylooking for pixel “holes” in a tear film image that were unmatched witha TFLT palette, such as described above with regard to thepost-processing of the tear film image (block 1037). Unmatched pixelscan be indicative of noise or errant data in a pixel. The pixels thatwere unmatched with the TFLT palette that are surrounded by pixels thatwere able to be matched with the TFLT palette are indicative of theunmatched pixel representing errant data, such as noise. This is becausethe tear film does not vary substantially between neighboring pixels, sothe unmatched pixel can be assumed to be errant or noise. If unmatchedpixels exist in the tear film image (decision 1039), for each pixel holethat was identified, the color color-based value of such pixel holes isreplaced by an average of neighboring pixels in the tear film image(block 1041). The average may be weighted. For example, FIG. 49Cillustrates a pixel weighting map 1047 that shows an exemplary weightingthat can be applied to the color-based value of neighboring pixels of apixel of interest. If a neighboring pixel is also unmatched to the TFLTpalette, such neighboring pixel is ignored in the use of averaging forthe pixel of interest.

With reference back to FIG. 49B, it may be desired to temporally filterthe tear film images after spatial filtering is performed (block 1045).Temporal filtering involves filtering pixels in a tear film image basedon the median value of the same pixel position in a temporal series oftear film images. The theory behind temporal filtering of the tear filmimage is that a pixel value for a given pixel location should not changesubstantially in a series of tear film images captured from a patient'socular tear film in a short period of time. For example, for a givenpixel x, y that is unmatched to a TFLT palette in frame n of a series oftear film images, the unmatched pixel x, y may be assigned a newcolor-based value based on a median of the same pixel x, y in the otherseries of tear film images. For example, neighboring tear film imagesmay be used, such as frames n−2 through frames n+2, so that a givenpixel x, y is assigned a median value that is from tear film imagescaptured just before and just after the tear film image with pixel x, yof interest. After spatial and/or temporal filtering of the tear filmimage is performed, the resulting filtered tear film image may befurther processed to provide additional post-processing features (block1035), examples of which will now be described below.

Psuedo-Color

For example, FIG. 50A is an exemplary image 1030 representinginterference interactions of specularly reflected light from a patient'stear film results after being processed with certain pre-processingfunctions, as previously described, including but not limited to erodeand dilate, to reduce or eliminate noise and ambiguous LLTs and spatialand temporal filtering (e.g., in FIG. 49B). However, as seen in theimage 1030, the different colors in the image 1030 representingdifferent interference interactions of specularly reflected light torepresent different LLTs 1032 may be of lower contrast and thus not aseasy to distinguish to the view. The colors in the image 1030 are colorsrepresenting the natural or nominal interference interactions ofspecularly reflected light of a patient's tear film. To make thedifferent colors in the image 1030 representing the interferenceinteractions of specularly reflected light of a patient's tear film moredistinguishable on a display to view, such as by a technician, theadditional step of psuedocoloring may be employed, as described below.

In this regard, FIG. 50B is an exemplary image 1034 that is apsuedocolor representation of the image 1030 in FIG. 50A representinginterference interactions of specularly reflected light from a patient'stear film results. One will note the higher, enhanced contrast and moredistinguishable colors present in the image 1034 representing the sameLLTs 1032 in FIG. 50A, but with psuedocolor LLTs 1036. Thus, thedifferent LLTs 1036 in the psuedocolor image 1034 may be more easilynoticeable and distinguished. The enhanced contrast between thepsuedocolor thickness levels makes thickness contours easily noticeable.

FIG. 51 is a flowchart illustrating an exemplary process of convertingan image representing interference interactions of specularly reflectedlight from a patient's tear film results, such as the image 1030 in FIG.50A, to a psuedocolor representation of the image, such as the image1034 in FIG. 50B. In this regard, the process begins with the imageframe subtraction of two images captured by the video camera 198 in theOSI device 170 in FIG. 16 to reduce or eliminate background noise, aspreviously described above in blocks 300 and 302 in FIG. 28 (also shownas block 302 in FIG. 51). Next, with the isolated frames 1040 of thepatient's tear film produced by image capture and backgroundsubtraction, the pre-processing step of blink detection can be performedon the isolated frames 1040 to remove frames with undesired blinks usingany of the previous blink detection and removal methods previouslydescribed above and with regard to block 308 in FIG. 28 (also shown asblock 308 in FIG. 51). With the isolated frames 1040 with blink framesremoved as a result of the blink detection and removal process, theresulting frames 1042 can be processed by the post-processing system 262previously described above in FIG. 38 to produce a LLT frame 1044representing interference interactions of specularly reflected lightfrom a patient's tear film results, which may be image 1030 in FIG. 50Aas an example (as shown in block 262 in FIG. 51). Next, the controlsystem 240 replaces the LLTs represented by each color-based value ineach pixel in the resulting LLT frame 1044 with a psuedocolor value(block 1046) to produce a psuedocolor image 1048 having psuedocolorvalues representing interference interactions of specularly reflectedlight from a patient's tear film results, before the process ends (block1050). For example, the psuedocolor image 1048 may be the image 1034 inFIG. 50B as an example.

FIG. 52 is a psuedocolor map 1052 illustrating exemplary conversions ofnominal RGB values 1054 representing colors of interference interactionsof specularly reflected light from a patient's tear film results fordifferent LLTs 1056, to psuedocolor RGB values 1058 representingpsuedocolors for the interference interactions of specularly reflectedlight from a patient's tear film for the LLTs 1056. Note that thepsuedocolor RGB values 1058 can be any values desired, but as shown inFIG. 52 are selected as RGB values that will result in higher contrastwhen displayed on a display. The RGB values 1058 are ideally selected tocover a wide range of psuedocolor RGB values 1058 to provide sufficientcolor separation between adjacent psuedocolor RGB values 1058representing adjacent LLTs 1056 to provide a higher contrast image.

The psuedocolor map 1052 can be stored in memory 258 in the OSI device170 in FIG. 16 to be accessed and employed by the control system 240therein to perform psuedocolor processing of a captured and processedimage containing interference interactions of specularly reflected lightfrom a patient's tear film. For example, the psuedocolor map 1052 can beemployed as part of block 1046 in FIG. 51 to replace the LLT representedby each color-based value in each pixel in the resulting LLT frame 1044with a psuedocolor value to produce the psuedocolor image 1048 havingpsuedocolor values representing interference interactions of specularlyreflected light from a patient's tear film.

3D Visualization

The above processes to measure LLT of a patient's tear film are usefulto provide an average LLT and to visually display the differences in LLTin two-dimensions using different color representations. These colorrepresentations can be nominal color-based values representinginterference interactions of specularly reflected light from a patient'stear film or psuedocolor values, as previously described. However, itmay be desired to provide other or additional methods of displayingdifferent LLTs of an image of a patient's tear film on the OSI device170 in FIG. 16 that would be useful to a technician. In this regard,three-dimensional (3D) visualization is another processing step that canbe performed on an image representing interference interactions ofspecularly reflected light from a patient's tear film after beingprocessed with pre-processing functions to further assist a technicianin seeing differences in LLTs in different regions of a patient's tearfilm.

For example, FIG. 53 is an exemplary three-dimensional (3D)visualization image 1060 of a two-dimensional (2D) visualization imagerepresenting interference interactions of specularly reflected lightfrom a patient's tear film results after being processed withpre-processing functions. For example, the 3D visualization image 1060may be of the 2D visualization image 1030 of the patient's tear film inFIG. 50A. The 3D visualization image 1060 of the patient's tear film inFIG. 53 not only shows different LLTs represented by nominal color-basedvalues representing different interference interactions of specularlyreflected light from a patient's tear film, but these differentcolor-based values are shown as different heights in the 3Dvisualization image 1060. In this manner, a technician can easilydistinguish the different LLTs in different regions of interest in the3D visualization image 1060 visually as different heights or contours inthe 3D visualization image 1060. Note that although the 3D visualizationimage 1060 in FIG. 53 is shown using nominal color-based valuerepresentations interference interactions of specularly reflected lightfrom a patient's tear film, the 3D visualization image 1060 can also beprocessed using the psuedocolor processing method described above toproduce the same image with color-based values represented aspsuedocolor values.

FIG. 54 is a flowchart illustrating an exemplary process for convertinga 2D visualization image representing interference interactions ofspecularly reflected light from a patient's tear film results into a 3Dvisualization image, such as 3D visualization image 1060 in FIG. 53. Inthis regard, the process begins with the image frame subtraction of twoimages captured by the video camera 198 in the OSI device 170 in FIG. 16to reduce or eliminate background noise, as previously described abovein blocks 300 and 302 in FIG. 28 (also shown as block 302 in FIG. 54).Next, with the isolated frames 1040 of the patient's tear film producedby image capture and background subtraction, the pre-processing step ofblink detection can be performed on the isolated frames 1040 to removeframes with undesired blinks using any of the previous blink detectionand removal methods previously described above and with regard to block308 in FIG. 28 (also shown as block 308 in FIG. 54). With the isolatedframes 1040 with blink frames removed as a result of the blink detectionand removal process, the resulting frames 1042 can be processed by thepost-processing system 262 previously described above in FIG. 38 toproduce a LLT frame 1044 representing interference interactions ofspecularly reflected light from a patient's tear film results, which maybe image 1030 in FIG. 50A as an example (as shown in block 262 in FIG.54). Next, the control system 240 replaces the LLTs represented by eachcolor-based value in each pixel in the resulting LLT frame 1044 with acorresponding height (block 1062) to produce a 3D visualization image1064 having 3D visualizations representing interference interactions ofspecularly reflected light from a patient's tear film results, beforethe process ends (block 1066). For example, the 3D visualization image1064 produced by the process may be the 3D visualization image 1060 inFIG. 53 as an example.

FIG. 55 is a 3D visualization conversion map 1068 illustrating anexemplary conversion of LLTs 1070 represented by different RGBcolor-based values 1072 to height values 1074 used to provide a heightdimension to each pixel represented in a 2D visualization image toprovide a 3D visualization image. As illustrated therein, a 3Dvisualization map 1068 is shown that contains a different height value1074 is assigned to a different LLT 1070 in the table 1069. For example,the 3D visualization map 1068 may be stored in memory 258 in the OSIdevice 170 in FIG. 16 to be accessed and employed by the control system240 therein to perform 3D visualization processing of a captured andprocessed image containing interference interactions of specularlyreflected light from a patient's tear film. The 3D visualization map1068 is visually represented in FIG. 55 as the 3D visualization graph1076. As shown therein, the LLT values 1070 represented on the X-axisare provided, with the 3D visualization height values 1074 provided onthe Y-axis, to show the different height values 1074 assigned to eachLLT represented by the RGB color-based value 1072 in the 3Dvisualization map 1068.

The 3D visualization image 1060 in FIG. 53 described above representinginterference interactions of specularly reflected light from a patient'stear film results into different height values is useful to show andunderstand the LLT in different regions of a patient's tear film. The 3Dvisualization image 1060 in FIG. 53 is a single image. It may also bedesired to understand the change in LLT of a patient's tear film over adefined period of time. Said another way, it may be desired tounderstand the shape and change of shape, or the motion or velocity ofthe movement of lipid layer of a patient's tear film, which may berepresented by different LLTs over that period of time. However,providing this information numerically may be different for a technicianto easily interpret. It may be desired to visually provide thisinformation to a technician on the display of the OSI device 170 in FIG.16 as an example.

In this regard, FIGS. 56A-56D illustrate a series of exemplary 3Dvisualization images 1080A-1080D, respectively, of a series ofcorresponding 2D visualization images captured over a time periodrepresenting interference interactions of specularly reflected lightfrom a patient's tear film results after being processed withpre-processing functions over time. These 3D visualization images1080A-1080D can be shown in series on the display of the OSI device 170in FIG. 16 to show the velocity of movement of a patient's lipid layerover the tear film as represented by the change in LLTs in the series of3D visualization images 1080A-1080D. These 3D visualization images1080A-1080D can be produced by the 3D visualization processed describedabove.

Peak Detection

While a series of visualization images of interference interactions ofspecularly reflected light from a patient's tear film can be viewed todetermine the change in tear film and LLT of the tear film, whether as2D or 3D visualizations, it may also be desired to understand the peakLLT in a given region of interest of a patient's tear film. In otherwords, it may be desired to know the maximum LLT for each region ofinterest in a patient's tear film, instead of an average LLT or changein LLTs over time, as examples. This is because as the LLT changesdynamically over the course of an inter-blink period it may be difficultto determine the overall lipid coverage over this period. For example,FIG. 57A shows a series of images that show a hypothetical wave oflipids 1081 moving across a point 1083 on an eye surface. During peakdetection, a marker measures and retains the maximum LLT which has agiven point, such as point 1083 in FIG. 57A. Peak detection can bethought of as placing such a marker at every pixel in a tear film image.The markers are reset at each blink in the tear film image.

In this regard, FIG. 57B is an exemplary 2D visualization image 1082representing peak LLT values detected over a series of images ofinterference interactions of specularly reflected light from a patient'stear film results after being processed with certain pre-processingfunctions. As can be seen in the 2D visualization image 1082 in FIG. 57,each pixel is represented by a color-based value that represents a peakLLT detected over a period of time over a series of images ofinterference interactions of specularly reflected light from a patient'socular tear film. The 2D visualization image 1082 provides the highestLLT at any spatial location of the patient's tear film during the courseof a blink. The 2D visualization image 1082 is a composite view of theentire blink interval for a patient's tear film. Thus, as shown by theexemplary image 1082 in FIG. 57B, peak detection in a tear film imagecan provide a method for accessing lipid coverage and readily detectingirregularities in lipid layer distribution, which may be indicative ofmeibomian gland disease or ocular surface abnormalities. Psuedocolorprocessing can also optionally be provided to the 2D visualization image1082, as described above, if desired.

FIG. 58 is a flowchart illustrating an exemplary process for convertinga series of images of interference interactions of specularly reflectedlight from a patient's tear film results after being processed withpre-processing functions into an image representing peak LLT values,such as the 2D visualization image 1082 in FIG. 57. In this regard, theprocess begins with the image frame subtraction of two images capturedby the video camera 198 in the OSI device 170 in FIG. 16 to reduce oreliminate background noise, as previously described above in blocks 300and 302 in FIG. 28 (also shown as block 302 in FIG. 58). Next, with theisolated frames 1040 of the patient's tear film produced by imagecapture and background subtraction, the pre-processing step of blinkdetection can be performed on the isolated frames 1040 to remove frameswith undesired blinks using any of the previous blink detection andremoval methods previously described above and with regard to block 308in FIG. 28 (also shown as block 308 in FIG. 58). With the isolatedframes 1040 with blink frames removed as a result of the blink detectionand removal process, the resulting frames 1042 can be processed by thepost-processing system 262 previously described above in FIG. 38 toproduce a LLT frame 1044 representing interference interactions ofspecularly reflected light from a patient's tear film results, which maybe image 1030 in FIG. 50A as an example (as shown in block 262 in FIG.58).

Next, with continuing reference to FIG. 58, the first frame of aninterblink period over a series of captured images representinginterference interactions of specularly reflected light from a patient'stear film is selected as the current frame 1086 (block 1084). The firstframe as the current frame 1086 will contain the peak LLT values,because it is the first frame. The control system 240 will thendetermine from the subsequent series of captured frames if the LLTvalues in each pixel are greater than the current stored peak LLTvalues. In this regard, the control system 240 determines if thecorresponding pixel of the next image in the series of captured imagesrepresenting interference interactions of specularly reflected lightfrom a patient's tear film has a greater LLT (block 1088). If not, thecontrol system 240 keeps the current pixel as having the peak LLT (block1090). If the corresponding pixel of the next image in the series ofcaptured images representing interference interactions of specularlyreflected light from a patient's tear film has a greater LLT, thecontrol system 240 will replace that pixel in the current frame 1086with the greater LLT value (block 1092). A new frame is created usingthe peak LLT values stored for each pixel (block 1094). The processcontinues using each subsequent frame captured in a given interblinkperiod until a final resulting peak detection image presenting peak LLTsof interference interactions of specularly reflected light from apatient's tear film is produced (blocks 1096 and 1098).

FIG. 59 is a table 1099 illustrating an exemplary conversion of RGBvalues of specularly reflected light from a patient's tear film resultsinto a corresponding LLT that may be used to determine peak valueswithin images of a patient's tear film;

FIGS. 60A-60I are a series of exemplary images 1082(A)-1082(I),respectively, representing peak values detected over a series of imagesof interference interactions of specularly reflected light from apatient's tear film results after being processed with pre-processingfunctions, as peak values change over time. For example, a first imageof the peak values of the interference interactions of specularlyreflected light from a patient's tear film results is shown in FIG. 60Aas image 1082(A). The first image will be deemed to have peak valuessince no other images are yet processed. As subsequent images of theinterference interactions of specularly reflected light from a patient'stear film are analyzed, a separate image is stored that represents peakvalues detected. The series of images 1082(B)-1082(I) representexemplary images of peak values of interference interactions ofspecularly reflected light from a patient's ocular tear film.

Thus, in this example, the peak detection processing of a tear filmimage successively goes through each frame during a given period,setting the peak value at each pixel equal to the maximum LLT value ofthat pixel up to the current frame. This creates a video (set of frames)which, rather than showing the LLT for each pixel at each point in time,shows the maximum LLT for each pixel up to the current point in time(e.g., images 1082(A)-1082(I) in FIGS. 60A-60I). This process alsocreates a static image (the final frame) (e.g., image 1082 in FIG. 57B),which depicts the maximum LLT of each pixel over the entire inter-blinkperiod.

Tear Film Thickness (TFT) Stabilization

It may also be desired to know if a patient's tear film is stable orunstable between eye blinks. For example, regions of the patient's tearfilm may have high peak LLTs during the course of an interblink, but itmay be desired to know if these LLTs are present during short or longerperiods of time on a patient's tear film during blinks. In other words,it may be desired to know how stable or unstable a patient's tear filmis over an interblink period. Stability or instability of a patient'slipid layer over an interblink period can be an indication of theaqueous layer of the patient's tear film. The theory is that how apatient's tear film moves during a series of tear film images during aninterblink period is an indication of the patient's aqueous layerthickness. The aqueous layer provides a transport layer by which thelipid layer moves. The faster a patient's lipid layer stabilizes, theless aqueous layer is present in the patient's tear film. The slower thepatient's lipid layer stabilizes, the more aqueous layer is present inthe patient's tear film. Thus, it may be desired to determine a settlingtime of the lipid layer during an interblink period as a indirect methodto measure ALT or determine aqueous layer characteristics.

In this regard, FIG. 61 is an exemplary tear film stabilization graph1100 that can be processed by the control system 240 and displayed onthe display of the OSI device 170 in FIG. 16 to represent a patient'stear film thickness stabilization between eye blinks. In this regard,the graph 1100 contains two axis. The X-axis is time. The Y-axis isthickness measurements in micrometers (μm). A series of tear filmstability images 1102A-1102E are shown, with represent tear filmstability of the patient's tear film between blinks 1104A-1104D, whichare represented by areas of void where no tear film stabilityinformation is present. Each tear film stability image 1102A-1102Econtains a lipid layer portion 1106 and aqueous portion 1108representing LLT and ALT of the patient's tear film over time betweenblinks, respectively. As illustrated in the legend below tear filmstability image 1102D, the blink portion 1104 is a period of time inwhich tear film information is not present, due to blink removal. Theunstable portion 1110 of the tear film stability image 1102D is theperiod of time between blinks where the LLT and ALT of the patient'stear film is changing significantly and thus is unstable. The stableportion 112 of the tear film stability image 1102D is the period of timebetween blinks where the LLT and ALT of the patient's tear film is notchanging significantly and thus is stable.

FIG. 62A is a flowchart illustrating an exemplary process fordetermining a change in a patient's tear film thickness following eyeblinks indicative of a patient's tear film thickness stabilizationfollowing eye blink. A change in a patient's lipid layer thicknessfollowing eye blinks is indicative of a patient's tear film thicknessstabilization following eye blink. The change in the patient's lipidlayer thickness following eye blinks indicative of a patient's tear filmthickness stabilization following eye blink can be used to measure ALT.In this regard, the control system 240 in the OSI device 170 in FIG. 16detects an initial frame captured by the video camera 198 of thepatient's tear film following a detected eye blink (block 1120). Thecontrol system 240 saves the initial frame as frame N (block 1122). Thecontrol system 240 then subtracts the average LLT and ALT between thecurrent frame N and a subsequent frame in a series of captured images ofthe patient's tear film (block 1124). This difference in average LLT andALT in the consecutive images is then compared to a predefinedstablization value. The control system 240 determines if the differencein average LLT and ALT in the consecutive images is greater than thepredefined stablization value for a defined number of consecutive frames(block 1126). If not, the control system 240 processes the next image inthe series of captured images of the patient's tear film before the nextblink (blocks 1128-1126). If the control system 240 determines thedifference in average LLT and ALT in the consecutive images is greaterthan the predefined stabilization value for a defined number ofconsecutive frames in block 1126, the control system 240 sets thestabilization time of the patient's tear film as the difference betweenthe average LLT and ALT between images in which the difference inaverage LLT and ALT in consecutive images is greater than the predefinedstabilization value (block 1130), and the process ends (block 1132).These stabilization times can be used as stabilization values to berepresented in the tear film stabilization graph 1100 in FIG. 61.

FIG. 62B is a flowchart illustrating another exemplary process fordetermining a change in a patient's lipid layer thickness following eyeblinks indicative of a patient's tear film thickness stabilizationfollowing eye blink. The change in the patient's lipid layer thicknessfollowing eye blinks indicative of a patient's tear film thicknessstabilization following eye blink can be used to measure ALT. In thisregard, for a given interblink period in a series of tear film imagesfor tear film stabilization to be analyzed, the average LLT in the firstframe and final frame are determined (block 1150). A settling value isdetermined for a given percentage of decline in slope of the LLT (e.g.,90%) as an indication of the settling time of the lipid layer (block1152). The first frame in the tear film images for the interblink periodin which the LLT reaches the settling value is determined (block 1154).The final LLT value can be greater or smaller than the initial value, sothe LLT may reach the settling value in a positive or negativedirection. Thereafter, the settling time is calculated as the timebetween the initial frame and the first frame in which the LLT reachesthe settling value (block 1156).

FIG. 62C is a flowchart illustrating another exemplary process fordetermining a change in a patient's lipid layer thickness following eyeblinks indicative of a patient's tear film thickness stabilizationfollowing eye blink. The change in the patient's lipid layer thicknessfollowing eye blinks indicative of a patient's tear film thicknessstabilization following eye blink can be used to measure ALT. In thisexample, for each frame in a series of tear film images in an interblinkperiod, the motion of the lipid layer is determined by subtracting theLLT in a given tear film image frame from a previous tear film imageframe (block 1158). The maximum and minimum LLT motion values aredetermined during the interblink period (block 1160). A settling valueis determined for a given percentage of decline in slope of the LLT(e.g., 90%) as an indication of the settling time of the motion of thelipid layer (block 1152). The first frame in the tear film images forthe interblink period in which the LLT reaches the settling value isdetermined. The first frame in the tear film images for the interblinkperiod in which the motion of the lipid layer the settling value isdetermined (block 1164). The settling time of the lipid layer motion isdetermined as the time between the initial frame and the first frame inwhich the lipid layer motion reaches the settling value (block 1166).

Velocity Vector Map

It may also be desired provide a method for a technician to determinethe direction of movement of a patient's tear film between eye blinks asanother method to determine characteristics of the patient's tear film.Understanding the direction of movement of the tear film, including thelipid layer, may assist in understanding how the tear film isdistributed across the patient's eye. In this regard, a velocity vectorimage representing interference interactions of specularly reflectedlight from a patient's tear film, such as image 1030 in FIG. 50A, can beprovided, but with additional velocity vector information 1142superimposed on the image. The velocity vectors show the direction andmagnitude of velocity of the patient's tear film over a defined periodof time, such as between eye blinks. The length of the velocity vectorrepresents magnitude of velocity. The direction of the velocity vectorrepresents the direction of movement of the patient's tear film over thedefined period of time. In other words, the velocity vector informationprovides a “wind map” of the patient's tear film that can be used tovisualize direction and amplitude of movement of the patient's tearfilm.

Meniscus Height

Other methods may be employed to determine characteristics of apatient's tear film. For example, the OSI device 170 in FIG. 16 couldalso be used to measure the height of the meniscus of a patient's eye 11to be used to approximate the ALT of the patient's tear film. Forexample, FIG. 63 illustrates a side view of a patient's eye 11 in FIGS.1-3 described above. Common element numbers are shown to include commonfeatures. The meniscus 1150 of the eye 11 is shown therein. The videocamera 198 of the OSI device 170 in FIG. 16 could be used to image themeniscus 1150. The interference interactions of specularly reflectedlight from the meniscus 1150 may be correlated to a tear volume, whichmay be correlated to an ALT of the aqueous layer 14 of the patient'stear film.

Partial Blink Detection and Analysis

Further, dry eye sufferers may be affected in their abilities to performeveryday activities due to the persistent irritation and eye strain thatcan occur as a result of long periods of computer terminal use.Deficiency in the lipid layer thickness of the eye can be exasperated bypartial or incomplete blinking. Referring to FIGS. 2B and 62, it hasalso been discovered that eye blinks resulting in the upper eyelid 22coming down to meet the lower eyelid 24 of the patient's eye 11stimulate the meibomian glands 20 to secrete mebum to produce the lipidlayer 12 of the tear film. A partial eye blink where the upper and lowereyelids 22, 24 do not fully meet may not property stimulate themeibomian glands 20 to secrete mebum to produce a sufficient lipid layer12 to prevent or reduce evaporative dry eye. For example, FIG. 2B showsa partial eye blink of the patient's eye 11 where the upper and lowereyelids 22, 24 do not fully meet to close the eye 11 completely. Partialeye blinks may be particularly an issue in patients that wear contactlenses. The contact lens disposed over the tear film and cornea 10 canresult in more partial eye blinks than would otherwise occur if contactlenses were not worn.

Also, the number of complete blinks would increase the height of theposition of gaze of the individual. So if an individual were looking ata computer which was ten (10) degrees above eye level, they would needmore complete blinks than if the computer were at eye level. Similarlyif the computer monitor were placed below eye level significantly, therewould be the need for fewer blinks because the rate of evaporation fromthe eye would decrease as the height of the exposed aperture decreases.These factors have been studied and published as work place safety andergonomic studies have indicated the effect of eye strain onproductivity and worker satisfaction. Besides eye level position, otherqualifiers are a factor, such as the context of the work, localhumidity, type of task, age, skin color, etc. of any one individual.

Thus, there is also a need to be able to observe blinking in astandardized method to determine whether or not the lids touched duringthe blinking process. The importance of the lipid layer on dry eyesyndrome has been well studied (See FIG. 1 for the lipid layer on thecornea of the eye). The blink of the upper eyelid can maintain asufficient lipid layer and the normal blink, defined by complete closureof the upper eyelid to the lower eyelid may not always occur.

In this regard, FIG. 2A shows an open eye 11 and FIG. 2B depicts a blinkof the eye 11. For the purposes of this discussion, there are two typesof blinks; the complete blink in which the upper eyelid makes contact onthe lower eyelid throughout the margin of the eyelid, and the partialblink in which a portion or all of the eyelid margin is not in contactwith each other. There needs to be a significant percentage of blinks tobe complete to maintain the normal lipid layer of the eye. It would beclinically useful to be able to observe blinking in a standardizedmethod to determine whether or not the lids touched during the blinkingprocess. It is only when lids are shut completely, and then reopened,that oil is released from the meibomian glands. The exact ratio of howmany blinks should be complete versus those that are partial blinks(i.e. where the lids do not touch) has never been determined. The studyof blink rate is voluminous but there has not been a quantifiable studyon the amplitude of the blink, types of blinks (complete versus partial)during a specific time periods, or the percentage of blinks thatadequately resurface the cornea with lipids. Determining the amount oftravel of the blink will indicate what is normal and not normal forthese patients. With this information, the clinician can better informpatients in regards to their symptoms or condition, provide eyelidexercises, or propose additional therapy to alleviate the symptoms ofdry eye. Currently, there is no standardized quantitative method foranalyzing partial blinking.

As will be discussed below, the identification of partial blinks alsoincludes the ratio of partial blinks to full blinks to be determined toprovide a blink efficiency for a patient.

It is important when studying dry eye to consider the efficacy ofresurfacing the tear film by the upper lid since the upper lidfrequently does not make a complete blink. The lower portion of thecornea is thus not as generously endowed and refurbished with anadequate tear layer as is the upper part of the cornea. If the upper liddoes not make a compete blink, the meniscus of the upper lid is lessbountiful than it would be if it were refurbished by contact with thelower lid meniscus, and subsequent supplementation of tear film andlipid from the lower meniscus. It is important to understand that sincethe lower portion of the cornea is not refurbished by the spreading ofthe tear film of the upper lid, it is at more risk for desiccation.

It is further necessary to understand that the distribution of new fluidover the eye is essentially a function of the upper lid traveling overthe entire surface of the cornea and meeting the lower lid. Meeting thelower lid is critically important because resting on the lower lid isthe meniscus of the lower lid; the meniscus resting on the lower lid issignificantly more bountiful than the meniscus of the upper lid. Thus,when the upper lid travels over the entire surface of the cornea on thedownward phase of the blink and meets the lower lid and then starts theupward phase, it carries fresh tears and fresh lipid over the cornealsurface as the upper lid in the upward phase of the blink literallydrags the fresh tears and fresh lipid upwards over the corneal andocular surfaces. Additionally, if the upper lid does not make a competeblink and touch the lower meniscus, the meniscus of the upper lid isthen less bountiful than it would be if it were refurbished by contactwith the lower lid meniscus, resulting in supplementation of tear filmand lipid from the lower meniscus.

Thus, in one embodiment, a zonular system for corneal exposure, such asthat in FIGS. 64A and 64B, may be used to divide the vertical dimensionof the exposed cornea into an arbitrary number of divisions, with onedivision starting at the extreme superior position at the upper lidmargin and upper lid meniscus, and continuing with a division at thelower position on the lower lid margin and meniscus. It is apparent thatstarting with the bottom division and working upward, there would be acorrelation for rewetting of the ocular surfaces by blinking, forexposure and for evaporation. The latter would be correlated to time.

Thus, if the upper lid does not traverse over the entire cornea and makecontact with the lower lid it is unable to properly refurbish the tearlayer and the lipid layer with the material in the inferior meniscus.The phenomenon where many of the blinks are partial compromises thelower portion and makes the development of a model and an index with anOSI device 170 or other imaging device essential for both research and aclinical understanding of the nature and the frequency of the blinknecessary to maintain an adequate layer of tears and an adequate layerof lipid. In addition, an OSI device of the type described herein allowsone to observe the decline in lipid layer thickness between blinks. Asmentioned previously, the requirement for tear film stability and theneed to resurface will vary with the nature of the tear film and lipidlayer and the age of the person and many other factors.

Referring back to FIGS. 2A and 2B, FIG. 2A shows an open eye and FIG. 2Bdepicts a blink. For the purposes of this discussion, there are twotypes of blinks; the complete blink in which the upper eyelid makescontact on the lower eyelid throughout the margin of the eyelid, and thepartial blink in which a portion or all of the eyelid margin is not incontact with each other. There needs to be a significant percentage ofblinks to be complete to maintain the normal lipid layer of the eye. Itwould be clinically useful to be able to observe blinking in astandardized method to determine whether or not the lids touched duringthe blinking process. It is only when lids are shut completely, and thenreopened, that oil is released from the meibomian glands. The exactratio of how many blinks should be complete versus those that arepartial blinks (i.e. where the lids do not touch) has never beendetermined. The study of blink rate is voluminous but there has not beena quantifiable study on the amplitude of the blink, types of blinks(complete versus partial) during a specific time periods, or thepercentage of blinks that adequately resurface the cornea with lipids.Determining the amount of travel of the blink will indicate what isnormal and not normal for these patients. With this information, theclinician can better inform patients, provide exercises, or proposeadditional therapy to alleviate the symptoms of dry eye. The OSI devicedescribed herein, or any other suitable imaging device, may be used toobserve blinking in a standardized method to determine whether or notthe lids touched during the blinking process, as described more fullybelow.

The method and apparatus described herein may include the OSI devicedescribed herein, or any other suitable imaging device, configured tocalculate the amplitude of blinks and determine whether eye lid margincontact was complete over a given time duration. This information can betied with the productivity of each blink in terms of enriching the lipidlayer thickness. Lid margin contact can be expressed as a percentage oftravel, for instance full contact could be considered 100% travel. As anexample, an upper eye lid travel that only reached the bottom of thepupil would be considered 60% travel. The OSI or other imaging devicewould record “no image” time durations during a complete blink and wouldalso calculate the percentage of surface area during partial imagingsegments.

FIG. 65A illustrates a complete blink and FIG. 65B shows an increasedaperture due to an upper gaze by the patient. FIG. 65C shows keylandmarks in the upcoming discussion: 1151—upper eyelid, 1157—distanceto the center of the pupil, and 1155—amplitude of upper eyelid travel.

Using videography and an illumination technique that provides diffuselight over the bottom third of the eye, an imaging device, such as theOSI device described herein in one embodiment, is used to record theamount of time in which no image is provided from the tear film onto therecording apparatus. This would allow an index to be developed thatwould be quantitative and provide more clinically relevant informationof how the upper eyelid came over the pupil. Since the OSI or otherimaging device, or any other instrument, will record the time that thereis no image from the tear film, a metric can be developed which totalsthe frequency and also amount of time of zero or partial image. Theaperture of the eye can be divided into a number of different recordingsegments. For example, as previously discussed, the surface of the eyecan be sectioned and segregated for calculation purposes as shown abovein FIGS. 64A-64D. FIG. 64A depicts the surface of the eye divided byhorizontal lines for observing and recording the amplitude of travel ofthe upper eyelid. FIGS. 64B-64D illustrate alternate embodiments ofsegmenting the surface of the eye and image for observing and recordingthe amplitude of upper eyelid travel.

Over a predetermined time duration, the number of complete and partialblinks can be recorded, studied, and analyzed as it pertains tocomplete, partial, or non-productive blinks. For example, an imagingapparatus in which the image on the eye can be observed, recorded andanalyzed by videography and computer software, like OSI device 170, isrelevant and applicable herein. To observe and record these ratios, thetime duration for analysis and recording the image on the eye may belong. For instance, a patient may be asked to stare at targets or imagesfor a predetermined time period while data collection is beingperformed.

As an example of determining the amplitude of upper eyelid travel, inthe eye open condition, the position of the upper eyelid can bedetermined and normalized by the center of the pupil position. As theupper eyelid travels downward, the surface area of an available imagewill decrease and can be recorded and analyzed. When no image isavailable to the imaging device, the blink is considered complete and ifa partial image is available along the margin of the eyelid, the blinkis categorized as partial. In addition, the resulting thickness of lipidlayer on the return travel of the upper eyelid can provide an indicationof the productivity of the travel of the upper eyelid.

In this regard, in one embodiment, a partial eye blink detection methodin an ocular tear film image or frame may be performed as follows. Forexample, to detect partial blinking, a first master frame may first becreated from a first frame of a frame pair of a blink frame sequence ofthe ocular tear film to track pixels and whether they change as aneyelid passes during a blink. For the first added color frame of a blink(identified using one of the above blink detection methods as anexample), the chroma and intensity of each pixel is calculated. Thechroma is equal to maximum RGB value minus minimum RGB value. Theintensity is provided as R²+G²+B². If a pixel has a chroma less than orequal to a predefined value (e.g., 25) and an intensity greater than apredefined value (e.g., 300), the corresponding pixel on the first frameof the ocular tear film is set to white color-based value. This meansthat this pixel is part of the specular reflection and has not beencovered by the eyelid. Next, the master frame can be eroded and with adisk of a desired radius (e.g., 5). If any pixels in the second frame nolonger meet the intensity and chroma criteria within the master frame(i.e. they are no longer showing specular reflection), the correspondingpixel is set to black in the master frame. The above process is thenrepeated for a blink sequence of frames until completed. The number ofpixels present in the master frame that are still white are calculated,meaning these pixels were not covered by an eyelid at any point duringthe blink sequence. The number of white pixels is compared to a presetthreshold (e.g., 0). If the number of uncovered pixels in the masterframe is greater than this threshold, the detected blink is labeled apartial blink.

The parameters that could be studied using the apparatuses and methodsdisclosed herein include:

1. Frequency of complete blinks versus partial blinks expressed as aratio.

2. Number of complete blinks within a time duration.

3. Amplitude of the blink or travel of the upper eyelid.

4. The number of incomplete blinks recorded and the percentage of theexposed aperture of the eye. Not all incomplete blinks are the same.Some incomplete blinks are more like an eyelid flutter and others arealmost complete blinks. The degree of incompleteness of eyelid blinkscan be categorized and set to an appropriate level of therapy.

5. The mean amount of exposed aperture during incomplete blinkingexpressed as a percentage of surface area.

6. The productivity of the blinks as determined by the thickness of theresulting lipid layer on the eye after the blink.

7. The percentage of productive blinks within a given time duration.

8. Other parameters such as the speed of the upper eyelid travel andtime duration in the closed position can be determined depending uponthe sample rate of the recording mechanism.

The apparatuses and methods disclosed herein could aid in quantifyingthese parameters for a given patient. Understanding these values couldbe of significant clinical importance for a patient suffering from dryeye.

The method and apparatus disclosed herein may utilize an OSI device,such as OSI device 170, as disclosed herein or any other suitableimaging device to calculate the amplitude of blinks and determinewhether eye lid margin contact was complete over a given time duration.This information can be tied with the productivity of each blink interms of enriching the lipid layer thickness. Lid margin contact can beexpressed as a percentage of travel, for instance full contact could beconsidered 100% travel. As an example, an upper eye lid travel that onlyreached the bottom of the pupil would be considered 60% travel. The OSIor other imaging device would record “no image” time durations during acomplete blink and would also calculate the percentage of surface areaduring partial imaging segments.

In this regard, embodiments disclosed herein can also include the OSIdevice 170 in FIG. 16 being employed to quantify the extent of partialeye blinks. For example, the video camera 198 can be controlled by thecontrol system 240 to capture images of the eye as previously discussed.Instead of eliminating frames that contain eye blinks, partial or not,in the series of images captured by the video camera 198 of thepatient's eye, the frames that do not contain eye blinks can beeliminated using any of the same blink detection methods as previouslydescribed above. The control system 240 can then process the remainingimages of the patient's eye that contain eye blinks to quantify the areaor distance between the upper and lower eyelids 22, 24 that do notresult in a full eye blink. For example, the control system 240 may beconfigured to distinguish pixels containing white color as the cornea,as an indication that the upper and lower eyelids 22, 24 are not presentin those portions of the images. The control system 240 may beconfigured to determine the area or distance between the upper and lowereyelids 22, 24 are the lowest point of the eye, which is representativeof the further distance the upper eyelid 22 may travel to close on thelower eyelid 24.

Graphical User Interface (GUI)

In order to operate the OSI device 170, a user interface program may beprovided in the user interface system 278 (see FIG. 25A) that drivesvarious graphical user interface (GUI) screens on the display 174 of theOSI device 170 in addition to the GUI utility 280 of FIG. 29 to allowaccess to the OSI device 170. Some examples of control and accesses havebeen previously described above. Examples of these GUI screens from thisGUI are illustrated in FIGS. 44-48 and described below. The GUI screensallow access to the control system 240 in the OSI device 170 and tofeatures provided therein. As illustrated in FIG. 64, a login GUI screen520 is illustrated. The login GUI screen 520 may be provided in the formof a GUI window 521 that is initiated when a program is executed. Thelogin GUI screen 520 allows a clinician or other user to log into theOSI device 170. The OSI device 170 may have protected access such thatone must have an authorized user name and password to gain access. Thismay be provided to comply with medical records and privacy protectionlaws. As illustrated therein, a user can enter their user name in a username text box 522 and a corresponding password in the password text box524. A touch or virtual keyboard 526 may be provided to allowalphanumeric entry. To gain access to help or to log out, the user canselect the help and log out tabs 528, 530, which may remain resident andavailable on any of the GUI screens. After the user is ready to login,the user can select the submit button 532. The user name and passwordentered in the user name text box 522 and the password text box 524 areverified against permissible users in a user database stored in the diskmemory 268 in the OSI device 170 (see FIG. 25A).

If a user successfully logs into the OSI device 170, a patient GUIscreen 534 appears on the display 174 with the patient records tab 531selected, as illustrated in FIG. 67. The patient GUI screen 534 allows auser to either create a new patient or to access an existing patient. Anew patient or patient search information can be entered into any of thevarious patient text boxes 536 that correspond to patient fields in apatient database. Again, the information can be entered through thevirtual keyboard 526, facilitated with a mouse pointing device (notshown), a joystick, or with a touch screen covering on the display 174.These include a patient ID text box 538, patient last name text box 540,patient middle initial text box 542, a patient first name text box 544,and a date of birth text box 546. This data can be entered for a newpatient, or used to search a patient database on the disk memory 268(see FIG. 25A) to access an existing patient's records. The OSI device170 may contain disk memory 268 with enough storage capability to storeinformation and tear film images regarding a number of patients.Further, the OSI device 170 may be configured to store patientinformation outside of the OSI device 170 on a separate local memorystorage device or remotely. If the patient data added in the patienttext boxes 536 is for a new patient, the user can select the add newpatient button 552 to add the new patient to the patient database. Thepatients in the patient database can also be reviewed in a scroll box548. A scroll control 550 allows up and down scrolling of the patientdatabase records. The patient database records are shown as being sortedby last name, but may be sortable by any of the patient fields in thepatient database.

If a patient is selected in the scroll box 548, which may be an existingor just newly added patient, as illustrated in the GUI screen 560 inFIG. 68, the user is provided with an option to either capture new tearfilm images of the selected patient or to view past images, if past tearfilm images are stored for the selected patient on disk memory 268. Inthis regard, the selected patient is highlighted 562 in the patientscroll box 548, and a select patient action pop-up box 564 is displayed.The user can either select the capture new images button 566 or the viewpast images button 568. If the capture new images button 566 isselected, the capture images GUI 570 is displayed to the user under thecapture images tab 571 on the display 174, which is illustrated in FIG.69. As illustrated therein, a patient eye image viewing area 572 isprovided, which is providing images of the patient's eye and tear filmobtained by the video camera 198 in the OSI device 170. In this example,the image is of an overlay of the subtracted first and second tiledpattern images of the patient's tear film onto the raw image of thepatient's eye and tear film, as previously discussed. The focus of theimage can be adjusted via a focus control 574. The brightness level ofthe image in the viewing area 572 is controlled via a brightness control576. The user can control the position of the video camera 198 to alignthe camera lens with the tear film of interest whether the lens isaligned with the patient's left or right eye via an eye selectioncontrol 578. Each frame of the patient's eye captured by the videocamera 198 can be stepped via a stepping control 580. Optionally, or inaddition, a joystick may be provided in the OSI device 170 to allowcontrol of the video camera 198.

The stored images of the patient's eye and tear film can also beaccessed from a patient history database stored in disk memory 268. FIG.69 illustrates a patient history GUI screen 582 that shows a pop-upwindow 584 showing historical entries for a given patient. For each tearfilm imaging, a time and date stamp 585 is provided. The images of apatient's left and right eye can be shown in thumbnail views 586, 588for ease in selection by a user. The stored images can be scrolled upand down in the pop-up window 584 via a step scroll bar 590. Label namesin tag boxes 592 can also be associated with the images. Once a desiredimage is selected for display, the user can select the image to displaythe image in larger view in the capture images GUI 570 in FIG. 69.Further, two tear film images of a patient can be simultaneouslydisplayed from any current or prior examinations for a single patient,as illustrated in FIG. 71.

As illustrated in FIG. 71, a view images GUI screen 600 is shown,wherein a user has selected a view images tab 601 to display images of apatient's ocular tear film. In this view images GUI screen 600, bothimages of the patient's left eye 602 and right eye 604 are illustratedside by side. In this example, the images 602, 604 are overlays of thesubtracted first and second tiled pattern images of the patients tearfilm onto the raw image of the patient's tear eye and tear film, aspreviously discussed. Scroll buttons 606, 608 can be selected to move adesired image among the video of images of the patient's eye for displayin the view images GUI screen 600. Further, step and play controls 610,612 allow the user to control playing a stored video of the patient'stear film images and stepping through the patient's tear film images oneat a time, if desired. The user can also select an open patient historytab 614 to review information stored regarding the patient's history,which may aid in analysis and determining whether the patient's tearfilm has improved or degraded. A toggle button 615 can be selected bythe user to switch the images 602, 604 from the overlay view to just theimages 620, 622, of the resulting tiled interference interactions ofspecularly reflected light from the patient's tear films, as illustratedin FIG. 69. As illustrated in FIG. 72, only the resulting interferenceinteractions from the patient's tear film are illustrated. The user mayselect this option if it is desired to concentrate the visualexamination of the patient's tear film solely to the interferenceinteractions.

Many modifications and other embodiments of the disclosure set forthherein will come to mind to one skilled in the art to which thedisclosure pertains having the benefit of the teachings presented in theforegoing descriptions and the associated drawings. These modificationsinclude, but are not limited to, the type of light source orilluminator, the number of tiling groups and modes, the arrangement oftile groups, the type of imaging device, image device settings, therelationship between the illuminator and an imaging device, the controlsystem, the type of tear film interference model, and the type ofelectronics or software employed therein, the display, the data storageassociated with the OSI device for storing information, which may alsobe stored separately in a local or remotely located remote server ordatabase from the OSI device, any input or output devices, settings,including pre-processing and post-processing settings. Note thatsubtracting the second image from the first image as disclosed hereinincludes combining the first and second images, wherein like signalspresent in the first and second images are cancelled when combined.Further, the present disclosure is not limited to illumination of anyparticular area on the patient's tear film or use of any particularcolor-based value representation scheme.

Therefore, it is to be understood that the disclosure is not to belimited to the specific embodiments disclosed and that modifications andother embodiments are intended to be included within the scope of theappended claims. It is intended that the present disclosure cover themodifications and variations of this disclosure provided they comewithin the scope of the appended claims and their equivalents. Althoughspecific terms are employed herein, they are used in a generic anddescriptive sense only and not for purposes of limitation.

We claim:
 1. An apparatus for peak detection of a tear film layerthickness(es) (TFLT), comprising: a control system configured to:receive a plurality of images containing optical wave interference ofspecularly reflected light from a region of interest of an ocular tearfilm captured by an imaging device while illuminated by amulti-wavelength light source; convert at least a portion of each imageamong the plurality of images representing the optical wave interferenceof the specularly reflected light from at least a portion of the regionof interest of the ocular tear film into at least one color-based value;measure the TFLT of the at least a portion of the region of interest ofthe ocular tear film in each image among the plurality of images basedon a comparison of the at least one color-based value to a tear filmlayer optical wave interference model; determine a peak TFLT from ameasured TFLT of the at least a portion of the region of interest of theocular tear film among the plurality of images; and generate a resultingimage comprising the peak TFLT for the at least a portion of the regionof interest of the ocular tear film.
 2. The apparatus of claim 1,wherein the control system is configured to, for each of the pluralityof images containing the optical wave interference of the specularlyreflected light from the region of interest: (a) receive at least onefirst image containing the optical wave interference of specularlyreflected light and a background signal from the region of interest ofthe ocular tear film captured by the imaging device while illuminated bythe multi-wavelength light source; (b) receive at least one second imagecontaining the background signal from the region of interest of theocular tear film captured by the imaging device; and (c) subtract the atleast one second image from the at least one first image to generate theresulting image containing the optical wave interference of specularlyreflected light from the region of interest of the ocular tear film withthe background signal removed or reduced.
 3. The apparatus of claim 2,further comprising the imaging device configured to capture the opticalwave interference of specularly reflected light and the backgroundsignal from the region of interest of the ocular tear film whileilluminated by the multi-wavelength light source in the at least onefirst image, and capture the background signal from the region ofinterest of the ocular tear film in the at least one second image. 4.The apparatus of claim 1, wherein the control system is furtherconfigured to detect whether an eyelid blink or eye movement wascaptured by the imaging device in the plurality of images.
 5. Theapparatus of claim 3, wherein the control system is further configuredto remove each image from the plurality of images capturing the eyelidblink or eye movement.
 6. The apparatus of claim 1, wherein the controlsystem is further configured to display the resulting image on adisplay.
 7. The apparatus of claim 1, wherein the resulting imagecomprises the peak TFLT for each pixel in the at least a portion of theregion of interest of the ocular tear film among the plurality ofimages.
 8. The apparatus of claim 1, wherein the control system isfurther configured to spatially filter the received plurality of imagescontaining the optical wave interference of specularly reflected lightfrom the region of interest of the ocular tear film.
 9. The apparatus ofclaim 1, wherein the control system is further configured to temporallyfilter the received plurality of images containing the optical waveinterference of specularly reflected light from the region of interestof the ocular tear film.
 10. The apparatus of claim 1, wherein the tearfilm layer optical wave interference model is comprised of a theoreticaltear film layer optical wave interference model.
 11. The apparatus ofclaim 1, wherein the at least one color-based value is comprised of atleast one red-green-blue (RGB) component value.
 12. The apparatus ofclaim 1, wherein the at least one color-based value is comprised of aplurality of color-based values representing a pixel among a pluralityof pixels in the region of interest of the ocular tear film in theresulting image.
 13. The apparatus of claim 1, wherein themulti-wavelength light source is comprised of a multi-wavelengthLambertian light source configured to uniformly or substantiallyuniformly illuminate the region of interest of the ocular tear film. 14.The apparatus of claim 1, wherein the control system is furtherconfigured to generate a psuedocolor image of the resulting image. 15.An apparatus for determining tear film stability of an ocular tear film,comprising: a control system configured to: receive a plurality ofimages containing optical wave interference of specularly reflectedlight from a region of interest of an ocular tear film captured by animaging device while illuminated by a multi-wavelength light source;convert at least a portion of each image among the plurality of imagesrepresenting the optical wave interference of the specularly reflectedlight from at least a portion of the region of interest of the oculartear film into at least one color-based value; measure a tear film layerthickness(es) (TFLT) of the at least a portion of the region of interestof the ocular tear film in each image among the plurality of imagesbased on a comparison of the at least one color-based value to a tearfilm layer optical wave interference model; and determine astabilization time of the ocular tear film based on the change in theTFLT in the at least a portion of the region of interest of the oculartear film in the plurality of images.
 16. The apparatus of claim 15,wherein the control system is configured to, for each of the pluralityof images containing the optical wave interference of the specularlyreflected light from the region of interest: (a) receive at least onefirst image containing the optical wave interference of specularlyreflected light and a background signal from the region of interest ofthe ocular tear film captured by the imaging device while illuminated bythe multi-wavelength light source; (b) receive at least one second imagecontaining the background signal from the region of interest of theocular tear film captured by the imaging device; and (c) subtract the atleast one second image from the at least one first image to generate theresulting image containing the optical wave interference of specularlyreflected light from the region of interest of the ocular tear film withthe background signal removed or reduced.
 17. The apparatus of claim 16,further comprising the imaging device configured to capture the opticalwave interference of specularly reflected light and the backgroundsignal from the region of interest of the ocular tear film whileilluminated by the multi-wavelength light source in the at least onefirst image, and capture the background signal from the region ofinterest of the ocular tear film in the at least one second image. 18.The apparatus of claim 15, wherein the control system is furtherconfigured to detect whether an eyelid blink or eye movement wascaptured by the imaging device in the plurality of images.
 19. Theapparatus of claim 18, wherein the control system is further configuredto remove each image from the plurality of images capturing the eyelidblink or eye movement.
 20. The apparatus of claim 1, wherein the controlsystem is further configured to generate a resulting image of the changein the TFLT of the ocular tear film in the at least a portion of theregion of interest of the ocular tear film in the plurality of images.21. The apparatus of claim 20, wherein the control system is furtherconfigured to display the resulting image on a display.
 22. Theapparatus of claim 15, wherein the control system is further configuredto determine the stabilization time of the ocular tear film by beingconfigured to: determine an average TFLT in the at least a portion ofthe region of interest of the ocular tear film for an initial frame anda final frame among the plurality of images; determine a settling valueof the TFLT based on a difference between an average LLT in the firstframe and the final frame among the plurality of images; and determinethe stabilization time based on time for the TFLT in the initial frameto reach the settling value.
 23. The apparatus of claim 15, wherein thecontrol system is further configured to determine the stabilization timeof the ocular tear film by being configured to: determine a motion valuein the at least a portion of the region of interest of the ocular tearfilm in each image among the plurality of images; determine a maximummotion value and a minimum motion value among the determined motionvalues among the plurality of images; determine a settling value of theTFLT based on a difference between the maximum motion value and theminimum motion value; and determine the stabilization time based on timefor the motion value in the initial frame to reach the setting value.24. The apparatus of claim 15, wherein the resulting image comprises apeak TFLT for each pixel in the at least a portion of the region ofinterest of the ocular tear film among the plurality of images.
 25. Theapparatus of claim 15, wherein the control system is further configuredto spatially filter the received plurality of images containing theoptical wave interference of specularly reflected light from the regionof interest of the ocular tear film.
 26. The apparatus of claim 15,wherein the control system is further configured to temporally filterthe received plurality of images containing the optical waveinterference of specularly reflected light from the region of interestof the ocular tear film.
 27. The apparatus of claim 15, wherein the tearfilm layer optical wave interference model is comprised of a theoreticaltear film layer optical wave interference model.
 28. The apparatus ofclaim 15, wherein the at least one color-based value is comprised of atleast one red-green-blue (RGB) component value.
 29. The apparatus ofclaim 15, wherein the at least one color-based value is comprised of aplurality of color-based values representing a pixel among a pluralityof pixels in the region of interest of the ocular tear film in theresulting image.
 30. The apparatus of claim 15, wherein themulti-wavelength light source is comprised of a multi-wavelengthLambertian light source configured to uniformly or substantiallyuniformly illuminate the region of interest of the ocular tear film. 31.The apparatus of claim 15, wherein control system is further configuredto generate a psuedocolor image of the resulting image.